Novel proteins and nucleic acids encoding same

ABSTRACT

Disclosed herein are nucleic acid sequences that encode novel polypeptides. Also disclosed are polypeptides encoded by these nucleic acid sequences, and antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids and proteins.

RELATED APPLICATIONS

[0001] This application claims priority from U.S. Ser. Nos. 60/251,459 filed Dec. 5, 2000; and 60/259,007 filed Dec. 29, 2000, each of which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] The invention generally relates to nucleic acids and polypeptides. More particularly, the invention relates to nucleic acids encoding novel G-protein coupled receptor (GPCR) polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.

SUMMARY OF THE INVENTION

[0003] The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. The novel nucleic acids and polypeptides are referred to herein as GPCR1, GPCR2, GPCR3, GPCR4, GPCR5, GPCR6, GPCR7, GPCR8, GPCR9, GPCR10, GPCR11, GPCR12, GPCR13 and GPCR14 nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as “GPCRX” nucleic acid or polypeptide sequences.

[0004] In one aspect, the invention provides an isolated GPCRX nucleic acid molecule encoding a GPCRX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33. In some embodiments, the GPCRX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a GPCRX nucleic acid sequence. The invention also includes an isolated nucleic acid that encodes a GPCRX polypeptide, or a fragment, homolog, analog or derivative thereof. For example, the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. The nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33. Also included in the invention is an oligonucleotide, e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a GPCRX nucleic acid (e.g., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33) or a complement of said oligonucleotide.

[0005] Also included in the invention are substantially purified GPCRX polypeptides (e.g., SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34). In certain embodiments, the GPCRX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human GPCRX polypeptide.

[0006] The invention also features antibodies that immunoselectively bind to GPCRX polypeptides, or fragments, homologs, analogs or derivatives thereof.

[0007] In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a GPCRX nucleic acid, a GPCRX polypeptide, or an antibody specific for a GPCRX polypeptide. In a further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.

[0008] In a further aspect, the invention includes a method of producing a polypeptide by culturing a cell that includes a GPCRX nucleic acid, under conditions allowing for expression of the GPCRX polypeptide encoded by the DNA. If desired, the GPCRX polypeptide can then be recovered.

[0009] In another aspect, the invention includes a method of detecting the presence of a GPCRX polypeptide in a sample. In the method, a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound. The complex is detected, if present, thereby identifying the GPCRX polypeptide within the sample.

[0010] The invention also includes methods to identify specific cell or tissue types based on their expression of a GPCRX.

[0011] Also included in the invention is a method of detecting the presence of a GPCRX nucleic acid molecule in a sample by contacting the sample with a GPCRX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a GPCRX nucleic acid molecule in the sample.

[0012] In a further aspect, the invention provides a method for modulating the activity of a GPCRX polypeptide by contacting a cell sample that includes the GPCRX polypeptide with a compound that binds to the GPCRX polypeptide in an amount sufficient to modulate the activity of said polypeptide. The compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon containing) or inorganic molecule, as further described herein.

[0013] Also within the scope of the invention is the use of a therapeutic in the manufacture of a medicament for treating or preventing disorders or syndromes including, e.g., developmental diseases; MHCII and III diseases (immune diseases); taste and scent detectability disorders; Burkitt's lymphoma; corticoneurogenic disease; signal transduction pathway disorders; metabolic pathway disorders; retinal diseases including those involving photoreception; cell growth rate disorders; cell shape disorders; metabolic disorders; feeding disorders; control of feeding; the metabolic syndrome X; wasting disorders associated with chronic diseases; obesity; potential obesity due to over-eating or metabolic disturbances; potential disorders due to starvation (lack of appetite); diabetes; noninsulin-dependent diabetes mellitus (NIDDM1); infectious disease; bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2); pain; cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer); cancer-associated cachexia; anorexia; bulimia; asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; Crohn's disease; multiple sclerosis; Albright Hereditary Ostoeodystrophy; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; and psychotic and neurological disorders; including anxiety; schizophrenia; manic depression; delirium; dementia; neurodegenerative disorders; Alzheimer's disease; severe mental retardation; Dentatorubro-pallidoluysian atrophy (DRPLA); Hypophosphatemic rickets; autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome; immune disorders; adrenoleukodystrophy; congenital adrenal hyperplasia; hemophilia; hypercoagulation; idiopathic thrombocytopenic purpura; autoimmume disease; immunodeficiencies; transplantation; Von Hippel-Lindau (VHL) syndrome; stroke; tuberous sclerosis; hypercalceimia; cerebral palsy; epilepsy; Lesch-Nyhan syndrome; ataxia-telangiectasia; Leukodystrophies; Behavioral disorders; Addiction; Neuroprotection; cirrhosis; transplantation; systemic lupus erythematosus; emphysema; scleroderma; ARDS; renal artery stenosis; interstitial nephritis; glomerulonephritis; polycystic kidney disease; systemic lupus erythematosus; renal tubular acidosis; IgA nephropathy; cardiomyopathy; atherosclerosis; congenital heart defects; aortic stenosis; atrial septal defect (ASD); atrioventricular (A-V) canal defect; ductus arteriosus; pulmonary stenosis; subaortic stenosis; ventricular septal defect (VSD); valve diseases; scleroderma; fertility; pancreatitis; endocrine dysfunctions; growth and reproductive disorders; inflammatory bowel disease; diverticular disease; leukodystrophies; graft vesus host; hyperthyroidism; endometriosis; hematopoietic disorders and/or other pathologies and disorders of the like. The therapeutic can be, e.g., a GPCRX nucleic acid, a GPCRX polypeptide, or a GPCRX-specific antibody, or biologically-active derivatives or fragments thereof.

[0014] For example, the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders listed above and/or other pathologies and disorders.

[0015] The polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds. For example, a cDNA encoding GPCRX may be useful in gene therapy, and GPCRX may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions of the present invention will have efficacy for treatment of patients suffering the diseases and disorders listed above and/or other pathologies and disorders.

[0016] The invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., diseases and disorders listed above and/or other pathologies and disorders and those disorders related to cell signal processing and metabolic pathway modulation. The method includes contacting a test compound with a GPCRX polypeptide and determining if the test compound binds to said GPCRX polypeptide. Binding of the test compound to the GPCRX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.

[0017] Also within the scope of the invention is a method for screening for a modulator of activity, or of latency or predisposition to an disorders or syndromes including the diseases and disorders listed above and/or other pathologies and disorders or other disorders related to cell signal processing and metabolic pathway modulation by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes. The test animal expresses a recombinant polypeptide encoded by a GPCRX nucleic acid. Expression or activity of GPCRX polypeptide is then measured in the test animal, as is expression or activity of the protein in a control animal which recombinantly-expresses GPCRX polypeptide and is not at increased risk for the disorder or syndrome. Next, the expression of GPCRX polypeptide in both the test animal and the control animal is compared. A change in the activity of GPCRX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of the disorder or syndrome.

[0018] In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a GPCRX polypeptide, a GPCRX nucleic acid, or both, in a subject (e.g., a human subject). The method includes measuring the amount of the GPCRX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount of the GPCRX polypeptide present in a control sample. An alteration in the level of the GPCRX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject. Preferably, the predisposition includes diseases and disorders listed above and/or other pathologies and disorders. Also, the expression levels of the new polypeptides of the invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.

[0019] In a further aspect, the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a GPCRX polypeptide, a GPCRX nucleic acid, or a GPCRX-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition. In preferred embodiments, the disorder, includes the diseases and disorders listed above and/or other pathologies and disorders.

[0020] In yet another aspect, the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0022] Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The invention is based, in part, upon the discovery of novel nucleic acid sequences that encode novel polypeptides. The novel nucleic acids and their encoded polypeptides are referred to individually as GPCR1, GPCR2, GPCR3, GPCR4, GPCR5, GPCR6, GPCR7, GPCR8, GPCR9, GPCR10, GPCR11, GPCR12, GPCR13 and GPCR14. The nucleic acids, and their encoded polypeptides, are collectively designated herein as “GPCRX”.

[0024] The novel GPCRX nucleic acids of the invention include the nucleic acids whose sequences are provided in Tables 1A, 1C, 1E, 2A, 2C, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, inclusive, or a fragment, derivative, analog or homolog thereof. The novel GPCRX proteins of the invention include the protein fragments whose sequences are provided in Tables 1B, 1D, 1F, 2B, 2D, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B inclusive. The individual GPCRX nucleic acids and proteins are described below. Within the scope of this invention is a method of using these nucleic acids and peptides in the treatment or prevention of a disorder related to cell signaling or metabolic pathway modulation.

[0025] G-Protein Coupled Receptor proteins (“GPCRs”) have been identified as a large family of G protein-coupled receptors in a number of species. These receptors share a seven transmembrane domain structure with many neurotransmitter and hormone receptors, and are likely to underlie the recognition and G-protein-mediated transduction of various signals. Human GPCR generally do not contain introns and belong to four different gene subfamilies, displaying great sequence variability. These genes are dominantly expressed in olfactory epithelium. See, e.g., Ben-Arie et al., Hum. Mol. Genet. 1994 3:229-235; and, Online Mendelian Inheritance in Man (“OMIM”) entry # 164342(http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?).

[0026] The olfactory receptor (“OR”) gene family constitutes one of the largest GPCR multigene families and is distributed among many chromosomal sites in the human genome. See Rouquier et al., Hum. Mol. Genet. 7(9):1337-45 (1998); Malnic et al., Cell 96:713-23 (1999). Olfactory receptors constitute the largest family among G protein-coupled receptors, with up to 1000 members expected. See Vanderhaeghen et al., Genomics 39(3):239-46 (1997); Xie et al., Mamm. Genome 11(12):1070-78 (2000); Issel-Tarver et al., Proc. Natl. Acad. Sci. USA 93(20):10897-902 (1996). The recognition of odorants by olfactory receptors is the first stage in odor discrimination. See Krautwurst et al., Cell 95(7):917-26 (1998); Buck et al., Cell 65(1):175-87 (1991). Many ORs share some characteristic sequence motifs and have a central variable region corresponding to a putative ligand binding site. See Issel-Tarver et al., Proc. Natl. Acad. Sci. USA 93:10897-902 (1996).

[0027] Other examples of seven membrane spanning proteins that are related to GPCRs are chemoreceptors. See Thomas et al., Gene 178(1-2):1-5 (1996). Chemoreceptors have been identified in taste, olfactory, and male reproductive tissues. See id.; Walensky et al., J. Biol. Chem. 273(16):9378-87 (1998); Parmentier et al., Nature 355(6359):453-55 (1992); Asai et al., Biochem. Biophys. Res. Commun. 221(2):240-47 (1996).

[0028] The GPCRX nucleic acids of the invention encoding GPCR-like proteins include the nucleic acids whose sequences are provided herein, or fragments thereof. The invention also includes mutant or variant nucleic acids any of whose bases may be changed from the corresponding base shown herein while still encoding a protein that maintains its GPCR-like activities and physiological functions, or a fragment of such a nucleic acid. The invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described. The invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

[0029] The GPCRX proteins of the invention include the GPCR-like proteins whose sequences are provided herein. The invention also includes mutant or variant proteins any of whose residues may be changed from the corresponding residue shown herein while still encoding a protein that maintains its GPCR-like activities and physiological functions, or a functional fragment thereof. The invention further encompasses antibodies and antibody fragments, such as F_(ab) or (F_(ab))₂, that bind immunospecifically to any of the proteins of the invention.

[0030] The GPCRX nucleic acids and proteins are useful in potential therapeutic applications implicated in various GPCR-related pathological disorders and/or OR-related pathological disorders, described further below. For example, a cDNA encoding the GPCR (or olfactory-receptor) like protein may be useful in gene therapy, and the receptor -like protein may be useful when administered to a subject in need thereof. The nucleic acids and proteins of the invention are also useful in potential therapeutic applications used in the treatment of developmental diseases; MHCII and III diseases (immune diseases); taste and scent detectability disorders; Burkitt's lymphoma; corticoneurogenic disease; signal transduction pathway disorders; metabolic pathway disorders; retinal diseases including those involving photoreception; cell growth rate disorders; cell shape disorders; metabolic disorders; feeding disorders; control of feeding; the metabolic syndrome X; wasting disorders associated with chronic diseases; obesity; potential obesity due to over-eating or metabolic disturbances; potential disorders due to starvation (lack of appetite); diabetes; noninsulin-dependent diabetes mellitus (NIDDM1); infectious disease; bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2); pain; cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer); cancer-associated cachexia; anorexia; bulimia; asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; Crohn's disease; multiple sclerosis; Albright hereditary ostoeodystrophy; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; and psychotic and neurological disorders; including anxiety; schizophrenia; manic depression; delirium; dementia; neurodegenerative disorders; Alzheimer's disease; severe mental retardation; dentatorubro-pallidoluysian atrophy (DRPLA); hypophosphatemic rickets; autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome; immune disorders; adrenoleukodystrophy; congenital adrenal hyperplasia; hemophilia; hypercoagulation; idiopathic thrombocytopenic purpura; autoimmume disease; immunodeficiencies; transplantation; Von Hippel-Lindau (VHL) syndrome; stroke; tuberous sclerosis; hypercalceimia; cerebral palsy; epilepsy; Lesch-Nyhan syndrome; ataxia-telangiectasia; leukodystrophies; behavioral disorders; addiction; neuroprotection; cirrhosis; transplantation; systemic lupus erythematosus; emphysema; scleroderma; ARDS; renal artery stenosis; interstitial nephritis; glomerulonephritis; polycystic kidney disease; systemic lupus erythematosus; renal tubular acidosis; IgA nephropathy; cardiomyopathy; atherosclerosis; congenital heart defects; aortic stenosis; atrial septal defect (ASD); atrioventricular (A-V) canal defect; ductus arteriosus; pulmonary stenosis; subaortic stenosis; ventricular septal defect (VSD); valve diseases; scleroderma; fertility; pancreatitis; endocrine dysfunctions; growth and reproductive disorders; inflammatory bowel disease; diverticular disease; leukodystrophies; graft vesus host; hyperthyroidism; endometriosis; hematopoietic disorders and/or other pathologies and disorders. Other GPCR-related diseases and disorders are contemplated.

[0031] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR proteins and nucleic acids disclosed herein suggest that these olfactory receptors may have important structural and/or physiological functions characteristic of the olfactory receptor family. Therefore, the GPCR nucleic acids and proteins are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.

[0032] GPCR polypeptides are useful in the generation of antibodies that bind immunospecifically to the GPCR polypeptides of the invention, and as vaccines. The antibodies are for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the “Anti-GPCRX Antibodies” section below.

[0033] GPCR polypeptides can also be used to screen for potential agonist and antagonist compounds. For example, a cDNA encoding the GPCR-like protein may be useful in gene therapy, and the GPCR-like protein may be useful when administered to a subject in need thereof. By way of nonlimiting example, the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders. The novel nucleic acid encoding GPCR-like protein, and the GPCR-like protein of the invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.

[0034] GPCR1

[0035] GPCR1 includes three novel G-protein coupled receptor (“GPCR”) proteins disclosed below. The disclosed proteins have been named GPCR1a, GPCR1b and GPCR1c, and are related to olfactory receptors.

[0036] GPCR1a

[0037] The disclosed GPCR1a nucleic acid of 953 nucleotides (also referred to as SC35113271_A_da1) is shown in Table 1A. The disclosed GPCR1a open reading frame (“ORF”) begins with a TCT at nucleotides 2-4 which encodes a serine (the first amino acid of the mature protein) and ending with a TGA codon at nucleotides 950-952. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 1A GPCR1a nucleotide sequence. (SEQ ID NO:1) C TCTGCCATGATCATTTTCAACCTGAGCAGTTACAATCCAGCACCCTTCATTCTGGTAGGGATCCCAGG CCTGGAGCAATTCCATGTGTGGATTGGAATTCCCTTCTGTATCATCTACATTGTAGCTGTTGTGGGAAA CTGCATCCTTCTCTACCTCATTGTGGTGGAGCATAGTCTTCATGAACCCATGTTCTTCTTTCTCTCCAT GCTGGCCATGACTGACCTCATCTTGTCCACAGCTGGTGTGCCTAAAACACTCAGTATCTTTTGGCTAGG GGCTCGCGAAATCACATTCCCAGGATGCCTTACACAAATGTTCTTCCTTCACTATAACTTTGTCCTGGA TTCAGCCATTCTGATGGCCATGGCATTTGATCGCTATGTAGCTATCTGTTCTCCCTTGAGATATACCAC CATCTTGACTCCCAAGACCATCATCAAGAGTGCTATGGGCATCTCCTTTCGAAGCTTCTGCATCATCCT GCCAGATGTATTCTTGCTGACATGCCTGCCTTTCTGCAGGACACGCATCATACCCCACACATACTGTGA GCATATAGGTGTTGCCCAGCTCGCCTGTCCTGATATCTCCATCAACTTCTGGTATGGCTTTTGTCTTCC CATCATGACAGTCATCTCAGATGTGATTCTCATTGCTGTTTCCTACCCACACATCCTCTGTGCTGTCTT TTGCCTTCCCTCCCAAGATGCCCGCCAGAAAGCCCTCGGCACTTGTGGTTCTCATGTCTGTGTCATCCT CATGTTTTATACACCTGCCTTTTTCTCCATCCTCGCCCATCGCTTTGGACACAATGTCTCTCGCACCTT CCACATCATGTTTGCCAATCTCTACATTGTTATCCCACCTGCACTCAACCCCATGGTTTACGGAGTGAA GACCAAGCAGATCAGAGATAAGGTTATACTTTTGTTTTCTAAGGGTACAGGATGA T

[0038] The GPCR1a the nucleic acid sequence of this invention has 604 of 904 bases (66%) identical to a gb:GENBANK-ID:AF121975|acc:AF121975.1 mRNA from Mus musculus (Mus musculus odorant receptor S18 gene, complete cds) (E=2.4e−⁶⁸).

[0039] The disclosed GPCR1a polypeptide (SEQ ID NO: 2) encoded protein having 316 amino acid residues is presented in Table 1B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR1 a has a signal peptide and is likely to be localized at the endoplasmic reticulum (membrane) with a certainty of 0.6850. In other embodiments, it is localized at the plasma membrane with a certainty of 0.6400, at the Golgi body with a certainty of 0.4600 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR1 a peptide is between amino acids 45 and 46, at: VVG-NC. TABLE 1B Encoded GPCR1a protein sequence. (SEQ ID NO:2) SAMIIFNLSSYNPGPFILVGIPGLEQFHVWIGIPFCIIYIVAVVGNCILLYLIVVEHSLHEPMFFFLSMLANTDLIL STAGVPKTLSIFWLGAREITFPGCLTQMFFLHYNFVLDSAILMAMAFDRYVAICSPLRYTTILTPKTIIKSAMGISF RSFCIILPDVFLLTCLPFCRTRIIPHTYCEHIGVAQLACADISINFWYGFCVPIMTVISDVILIAVSYAHILCAVFC LPSQDARQKALGTCGSHVCVILMFYTPAFFSILAHRFGHNVSRTFHIMFANLYIVIPPALNPMVYGVKTKQIRDKVI LLFSKGTG

[0040] The disclosed GPCR1 a amino acid sequence of the protein of the invention was found to have 183 of 312 amino acid residues (58%) identical to, and 236 of 312 amino acid residues (75%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9WU89 protein from Mus musculus (Mouse) (ODORANT RECEPTOR S18) (E=3.3e⁻¹⁰¹).

[0041] GPCR1b

[0042] The disclosed GPCR1b nucleic acid of 953 nucleotides (also referred to as CG55798-03) is shown in Table 1C. The disclosed GPCR1b open reading frame (“ORF”) begins with an ATG at nucleotides 8-10 and ending with a TGA codon at nucleotides 950-952. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 1C GPCR1b nucleotide sequence. (SEQ ID NO:3) CTCTGCC ATGATCATTTTCAACCTGAGCAGTTACAATCCAGGACCCTTCATTCTGGTAGGGATCCCAGGCCTGG AGCAATTCCATGTGTGGATTGGAATTCCCTTCTGTATCATCTACATTGTAGCTGTTGTGGGAAACTGCATCCTT CTCTACCTCATTGTGGTGGAGCATAGTCTTCATGAACCCATGTTCTTCTTTCTCTCCATGCTGGCCATGACTGA CCTCATCTTGTCCACAGCTGGTGTGCCTAAAACACTCAGTATCTTTTGGCTAGGGGCTCGCGAAATCACATTCC CAGGATGCCTTACACAAATGTTCTTCCTTCACTATAACTTTGTCCTGGATTCAGCCATTCTGATGGCCATGGCA TTTGATCGCTATGTAGCTATCTGTTCTCCCTTGAGATATACCACCATCTTGACTCCCAAGACCATCATCAAGAG TGCTATGGGCATCTCCTTTCGAAGCTTCTGCATCATCCTGCCAGATGTATTCTTGCTGACATGCCTGCCTTTCT GCAGGACACGCATCATACCCCACACATACTGTGAGCATATAGGTGTTGCCCGGCTCGCCTGTGCTGATATCTCC ATCAACTTCTGGTATGGCTTTTGTGTTCCCATCATGACAGTCATCTCAGATGTGATTCTCATTGCTGTTTCCTA CGCACACATCCTCTGTGCTGTCTTTTGCCTTCCCTCCCAAGATGCCCGCCAGAAAGCCCTCGGCACTTGTGGTT CTCATGTCTGTGTCATCCTCATGTTTTATACACCTGCCTTTTTCTCCATCCTCGCCCATCGCTTTGGACACAAT GTCTCTCGCACCTTCCACATCATGTTTGCCAATCTCTACATTGTTATCCCACCTGCACTCAACCCCATGGTTTA CGGAGTGAAGACCAAGCAGATCAGAGATAAGGTTATACTTTTGTTTTCTAAGGGTACAGGATGA T

[0043] The GPCR1b the nucleic acid sequence of this invention has bases (66%) identical to a gb:GENBANK-ID:AF121975|acc:AF121975.1 mRNA from Mus musculus (Mus musculus odorant receptor S18 gene, complete cds) (E=1.2e−⁶⁸).

[0044] The disclosed GPCR1b polypeptide (SEQ ID NO: 4) encoded protein having 314 amino acid residues is presented in Table 1D using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR1b has a signal peptide and is likely to be localized at the endoplasmic reticulum (membrane) with a certainty of 0.6850. In other embodiments, it is localized at the plasma membrane with a certainty of 0.6400, at the Golgi body with a certainty of 0.4600 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR1b peptide is between amino acids 43 and 44, at: VVG-NC. TABLE 1D Encoded GPCR1b protein sequence. (SEQ ID NO:4) MIIFNLSSYNPGPFILVGIPGLEQFHVWIGIPFCIIYIVAVVGNCILLYLIVVEHSLHEPMFFFLSMLAMTDLILST AGVPKTLSIFWLGAREITFPGCLTQMFFLHYNFVLDSAILMAMAFDRYVAICSPLRYTTILTPKTIIKSAMGISFRS FCIILPDVFLLTCLPFCRTRIIPHTYCEHIGVARLACADISINFWYGFCVPIMTVISDVILIAVSYAHILCAVFCLP SQDARQKALGTCGSHVCVILMFYTPAFFSILAHRFGHNVSRTFHIMFANLYIVIPPALNPMVYGVKTKQ IRDKVILLFSKGTG

[0045] The disclosed GPCR1b amino acid sequence of the protein of the invention was found to have 184 of 310 amino acid residues (59%) identical to, and 234 of 310 amino acid residues (75%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9WU89 protein from Mus musculus (Mouse) (ODORANT RECEPTOR S18) (E=2.3e⁻¹⁰¹).

[0046] GPCR1c

[0047] The disclosed GPCR1c nucleic acid of 953 nucleotides (also referred to as CG55798-04) is shown in Table 1E. The disclosed GPCR1c open reading frame (“ORF”) begins with an ATG at nucleotides 8-10 and ending with a TGA codon at nucleotides 950-952. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions (underlined), if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 1E GPCR1c nucleotide sequence. (SEQ ID NO:5) CTCTGCC ATGATCATTTTCAACCTGAGCAGTTACAATCCAGGACCCTTCATTCTGGTAGGGATCCCAGGCCTGG AGCAATTCCATGTGTGGATTGGAATTCCCTTCTGTATCATCTACATTGTAGCTGTTGTGGGAAACTGCATCCTT CTCTACCTCATTGTGGTGGAGCATAGTCTTCATGAACCCATGTTCTTCTTTCTCTCCATGCTGGCCATGACTGA CCTCATCTTGTCCACAGCTGGTGTGCCTAAAACACTCAGTATCTTTTGGCTAGGGGCTCGCGAAATCACATTCC CAGGATGCCTTACACAAATGTTCTTCCTTCACTATAACTTTGTCCTGGATTCAGCCATTCTGATGGCCATGGCA TTTGATCACTATGTAGCTATCTGTTCTCCCTTGAGATATACCACCATCTTGACTCCCAAGACCATCATCAAGAG TGCTATGGGCATCTCCTTTCGAAGCTTCTCCATCATCCTGCCAGATGTATTCTTGCTGACATGCCTGCCTTTCT GCAGCACACGCATCATACCCCACACATACTGTGAGCATATGGGTGTTGCCCAGCTCGCCTGTGCTGATATCTCC ATCAACTTCTGGTATGGCTTTTGTGTTCCCATCATGACAGTCATCTCAGATGTGATTCTCATTGCTGTTTCCTA CGCACACATCCTCTGTGCTGTCTTTTGCCTTCCCTCCCAAGATGCCCGCCAGAAGGCCCTCGGCACTTGTGGTT CTCATGTCTGTGTCATCCTCATGTTTTATACACCTGCCTTTTTCTCCATCCTCGCCCATCGCTTTGGACACAAT GTCTCTCGCACCTTCCACATCATGTTTGCCAATCTCTACATTGTTATCCCACCTGCACTCAACCCCATGGTTTA CCGAGTGAAGACCAAGCAGATCAGAGATAAGGTTATACTTTTGTTTTCTAAGGGTACAGGATGA T

[0048] The GPCR1c the nucleic acid sequence of this invention has 604 of 904 bases (66%) identical to a gb:GENBANK-ID:AF121975|acc:AF121975.1 mRNA from Mus musculus (Mus musculus odorant receptor S18 gene, complete cds) (E=2.8e⁻⁶⁸).

[0049] The disclosed GPCR1 c polypeptide (SEQ ID NO: 6) encoded protein having 314 amino acid residues is presented in Table 1F using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR1c has a signal peptide and is likely to be localized at the endoplasmic reticulum (membrane) with a certainty of 0.6850. In other embodiments, it is localized at the plasma membrane with a certainty of 0.6400, at the Golgi body with a certainty of 0.4600 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR1c peptide is between amino acids 43 and 44, at: VVG-NC. TABLE 1F Encoded GPCR1c protein sequence. (SEQ ID NO:6) MIIFNLSSYNPGPFILVGIPGLEQFHVWIGIPFCIIYIVAVVGNCILLYLIVVEHSLHEPMFFFLSMLAMTDLILST AGVPKTLSIFWLCAREITFPGCLTQMFFLHYNFVLDSAILMAMAFDHYVAICSPLRYTTILTPKTIIKSAMGISFRS FCIILPDVFLLTCLPFCRTRIIPHTYCEHMGVAQLACADISINFWYGFCVPIMTVISDVILIAVSYAHILCAVFCLP SQDARQKALGTCGSHVCVILMFYTPAFFSILAHRFGHNVSRTFHIMFANLYIVIPPALNPMVYGVKTKQIRDKVILL FSKGTG

[0050] The disclosed GPCR1c amino acid sequence of the protein of the invention was found to have 181 of 310 amino residues (58%) identical to, and 233 of310 amino acid residues (75%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9WU89 protein from Mus musculus (Mouse) (ODORANT RECEPTOR S18) (E=4.9e⁻¹⁰⁰).

[0051] Possible small nucleotide polymorphisms (SNPs) found for NOV1b are listed in Tables 1G and 1H. Depth represents the number of clones covering the region of the SNP. The putative allele frequency (PAF) is the fraction of these clones containing the SNP. Silent indicates that the SNP results in no amino acid sequence change. A dash, when shown, means that a base is not present. The sign “>” means “is changed to.” TABLE 1G SNPs Consensus Base Position Depth Change PAF 621 18 T > C 0.278 680 18 T > C 0.389

[0052] TABLE 1H SNPs Amino Nucleotide Base Acid Base Position Change Position Change 97 A > G Silent N/A 254 A > G  83 Thr > Ala 313 A > G Silent N/A 378 G > A 124 Arg > His 385 A > G Silent N/A 631 A > G Silent N/A

[0053] Possible SNPs found for GPCR1c are listed in table 1I. TABLE 1I SNPs Consensus Base Position Depth Change PAF 254 17 A > G 0.294 378 18 G > A 0.278 559 12 A > G 0.250 631 11 G > A 0.455 692 11 G > T 0.455 713 11 T > C 0.455 721 11 A > G 0.455

[0054] GPCR1 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence.

[0055] The term GPCR1 is used to refer to all GPCR1 variants or members of the GPCR1 family disclosed herein unless we identify a specific family member or variant.

[0056] Nucleotide sequence homologies between the GPCR1 variants is shown in a Clustal W in Table 1J.

[0057] Amino acid sequence homologies between the GPCR1 variants is shown in a Clustal W in Table 1K.

[0058] The amino acid sequence of GPCR1 a has high homology to other proteins as shown in Table 1L. TABLE 1L BLASTX results for GPCR1a Smallest Sum High Prob Sequences producing High-scoring Segment Pairs: Reading Score P (N) ptnr: SPTREMBL-ACC:Q9WU89 ODOR RECP S18- Mus musculus, 321 aa 1005 3.3e−101

[0059] The disclosed GPCR1a has homology to the amino acid sequences shown in the BLASTP data listed in Table 1M. TABLE 1M BLASTP results for GPCR1a Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|9938014 ref|NP_064 Odorant receptor 321 183/312 236/312 1e−93 686.1| S18 gene [Mus musculus] (58%) (74%) gi|7305349 ref|NP_038 olfactory 326 178/298 226/298 2e−86 647.1| receptor 67 [Mus musculus] (59%) (75%) gi|9935442 ref|NP_064 odorant receptor 318 169/310 229/310 3e−82 688.1| S46 gene [Mus musculus] (54%) (73%) gi|14423837|sp|Q9H346 OLFACTORY 318 170/310 226/310 9e−81 |OYD1_HUMAN RECEPTOR 52D1 (54%) (72%) (HOR5′BETA14) gi|6532001 gb AAD2759 odorant receptor 339 158/290 206/290 2e−77 6.2 AF121976_1 S19 [Mus musculus] (54%) (70%)

[0060] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 1N.

[0061] The homologies shown above are shared by GPCR1a-GPCR1c insofar as GPCR1a, GPCR1b and GPCR1c are homologous as shown in Table 1K.

[0062] Table 1O lists the domain description from DOMAIN analysis results against GPCR2a. This indicates that the GPCR2a sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 10 Domain Analysis of GPCR1a gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:40) Length = 254 residues, 100% aligned Score = 81.6 bits (200), Expect = 6e−17 GPCR1a: 45 GNCILLYLIVVEHSLHEPMFFFLSMLAMTDLILSTAGVPKTLSIFWLGAREITFPGCLTQ 104 || +++ +|+    |  |   ||  ||+ ||+      |  |     |        | Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIGLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR1a: 105 MFFLHYNFVLDSAILMAMAFDRYVAICSPLRYTTILTPKTIIKSAMGISFRSFCIILPDV 164       |      +| |++ |||+||  ||||  | ||+      + +   +  + || + Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR1a: 165 FLLTCLPFCRTRIIPHTYCEHIGVAQLACADISINFWYGFCVPIMTVISDILIAVSYAH 224                          + +   +|    +   + ++ |    || + Gnl|Pfam|pfam00001: 121 LFSWLRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRA 180 GPCR1a: 225 ILCAVGCLPSQDARQKALGTCGSHVCVILMFYTPAFFSILA--HRFGHNVSRTGHIMFAN 282          |   |+ |       |  +| +       +|                ++ Gnl|Pfam|pfam00001: 181 RSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITL 240 GPCR1a: 283 LYIVIPPALNPMVY 296     +   |||++| Gnl|Pfam|pfam00001: 241 WLAYVNSCLNPIIY 254

[0063] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR1 proteins and nucleic acids disclosed herein suggest that these olfactory receptors may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for the treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders, cell shape disorders, feeding disorders, potential obesity due to over-eating, potential disorders due to starvation (lack of appetite), noninsulin-dependent diabetes mellitus ((NIDDM1)), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, allergies, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease, multiple sclerosis, Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, benign prostatic hypertrophy, psychotic and neurological disorders (including anxiety, schizophrenia, manic depression, delirium, dementia, and severe mental retardation), dentatorubro-pallidoluysian atrophy (DRPLA), hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome, as well as other diseases, disorders and conditions.

[0064] The disclosed GPCR1 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR1 epitope is from about amino acids 160 to 170. In additional embodiments, a GPCR1 epitope is from about amino acids 240 to 249, from about amino acids 260 to 270, from about amino acids 290 to 300 and from 305 to 310. The GPCR1 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0065] GPCR2

[0066] GPCR2 includes two GPCR proteins disclosed below. The disclosed proteins have been named GPCR2a and GPCR2b, and are related to olfactory receptors.

[0067] GPCR2a

[0068] The disclosed GPCR2a nucleic acid of 966 nucleotides (also referred to as AC011711_da2) is shown in Table 2A. The disclosed GPCR2a open reading frame (“ORF”) begins with a ATG at nucleotides 20-22 which encodes a serine (the first amino acid of the mature protein) and ending with a TAA codon at nucleotides 962-964. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 2A GPCR2a nucleotide sequence. (SEQ ID NO:7) CCCCTTGTCTCCTCACACA ATGACCCTGGGATCCCTCGGAAACACCAGCAGCAGCGTTTCTGCTACCTTCCTGCTGA GGGCATCCCTGGGCTGGAGCGCATGCACATCTGGATCTCCATCCCACTGTGCTTCATGTATCTGGTTTCCATCCCGG GCAACTGCACAATTCTTTTTATCATTAAAACAGAGCGCTCACTTCATGAACCTATGTATCTCTTCCTGTCCATGCTG GCTCTGATTGACCTGGGTCTCTCCCTTTGCACTCTCCCTACAGTCCTGGGCATCTTTTGGGTTGGAGCACGAGAAAT TAGCCATGATGCCTGCTTTGCTCAGCTCTTTTTCATTCACTGCTTCTCCTTCCTCGAGTCCTCTGTGCTACTGTCTA TGGCCTTTGACCGCTTTGTGGCTATCTGCCACCCCTTGCACTATGTTTCCATTCTCACCAACACAGTCATTGGCAGG ATTGGCCTCCTCTCTCTGGGTCGTAGTGTAGCACTCATTTTTCCATTACCTTTTATGCTCAAAAGATTCCCCTATTG TGGCTCCCCAGTTCTCTCACATTCTTATTGTCTCCACCAAGAAGTGATGAAATTGGCCTGTGCCGACATGAAGGCCA ACAGCATCTACGGCATGTTTGTCATCCTCTCTACAGTGGGTATAGACTCACTGCTCATCCTCTTCTCTTATGCTCTG ATCCTGCGCACCGTGCTGTCCATCGCCTCCAGGGCTGAGAGATTCAAGGCCCTTAACACCTGTGTTTCCCACATCTG TGCTGTGCTGCTCTTCTACACTCCCATGATTGGCCTCTCTGTCATCCATCGCTTTGGAAAGCACGCACCCCACCTGG TCCAGGTGGTCATGGGTTTCATGTATCTTCTCTTTCCTCCTGTGATGAATCCCATTGTCTACAGTGTGAAGACCAAA CAGATCCGGGATCGAGTGACGCATGCCTTTTGTTACTAA CT

[0069] The GPCR2 nucleic acid sequence of this invention has 586 of 883 bases (66%) identical to a gb:GENBANK-ID:AR009514|acc:AR009514.1 mRNA from Unknown. (Sequence 1 from patent U.S. Pat. No. 5,756,309) (E=4.1e⁻⁶⁷).

[0070] The disclosed GPCR2a polypeptide (SEQ ID NO: 8) encoded protein having 314 amino acid residues is presented in Table 2B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR2a has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6400. In other embodiments, it is localized at the Golgi body with a certainty of 0.4600, at the endoplasmic reticulum (membrane) with a certainty of 0.3700 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR2a peptide is between amino acids 49 and 50, at: NCT-IL. TABLE 2B Encoded GPCR2a protein sequence. (SEQ ID NO:8) MTLGSLGNSSSSVSATFLLSGIPGLERMHIWISIPLCFMYLVSIPGNCTILFIIKTERSLHEPMYLFLSMLALIDLG LSLCTLPTVLGIFWVGAREISHDACFAQLFFIHCFSFLESSVLLSMAFDRFVAICHPLHYVSILTNTVIGRIGLVSL GRSVALIFPLPFMLKRFPYCHSPVLSHSYCLHQEVMKLACADMKANSIYGMFVIVSTVGIDSLLILFSYALILRTVL SIASRAERFKALNTCBSHICAVLLFYTPMIGLSVIHRFGKQAPHLVQVVMGFMYLLFPPVMNPIVYSVKTKQIRDRV THAFCY

[0071] The disclosed GPCR2a amino acid sequence of the protein of the invention was found to have 171 of 305 amino acid residues (56%) identical to, and 219 of 305 amino acid residues (71%) similar to, the 320 amino acid residue ptnr:SPTREMBL-ACC:O88628 protein from Rattus norvegicus (Rat) (PUTATIVE G-PROTEIN COUPLED RECEPTOR RA1C) (E=3.7e⁻⁹²).

[0072] GPCR2b

[0073] The disclosed GPCR2b nucleic acid of 966 nucleotides (also referred to as CG50147-01) is shown in Table 2C. The disclosed GPCR2b open reading frame (“ORF”) begins with an ATG at nucleotides 20-22 and ending with a TAA codon at nucleotides 962-964. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 2C GPCR2b nucleotide sequence. (SEQ ID NO:9) CCCCTTGTCTCCTCACACA ATGACCCTGGGATCCCTGCGAAACAGCAGCAGCAGCGTTTCTGCTACCTTCCTGC TGAGTGGCATCCCTGGGCTCGAGCGCATGCACATCTGGATCTCCATCCCACTGTGCTTCATGTATCTGGTTTCC ATCCCGGGCAACTGCACAATTCTTTTTATCATTAAAACAGAGCGCTCACTTCATGAACCTATGTATCTCTTCCT GTCCATGCTGGCTCTGATTGACCTGGGTCTCTCCCTTTGCACTCTCCCTACAGTCCTGGGCATCTTTTGGGTTG GAGcACGACAAATTAGCCATGATGCCTGCTTTGCTCAGCTCTTTTTCATTCACTGCTTCTCCTTCCTCGAGTCC TCTGTGCTACTGTCTATGGCCTTTGACCGCTTTGTCGCTATCTGCCACCCCTTGCACTATGTTTCCATTCTCAC CAACACAGTCATTGGCAGGATTGGCCTCGTCTCTCTCGGTCGTAGTGTAGCACTCATTTTTCCATTACCTTTTA TGCTCAAAAGATTCCCCTATTGTCGCTCCCCAGTTCTCTCACATTCTTATTGTCTCCACCAAGAAGTGATGAAA TTGGCCTGTGCCGACATGAAGGCCAACAGCATCTACCGCATGTTTGTCATCGTCTCTACAGTGGGTATAGACTC ACTGCTCATCCTCTTCTCTTATGCTCTGATCCTGCGCACCGTGCTGTCCATCCCCTCCAGGGCTGAGACATTCA AGGCCCTTAACACCTGTGTTTCCCACATCTGTGCTGTGCTGCTCTTCTACACTCCCATGATTGGCCTCTCTGTC ATCCATCGCTTTGGAAAGCAGGCACCCCACCTGGTCCAGGTGGTCATGGGTTTCATGTATCTTCTCTTTCCTCC TGTGATGAATCCCATTGTCTACAGTGTGAAGACCAAACAGATCCGGGATCGAGTGACGCATGCCTTTTGTTACT AA CT

[0074] The disclosed GPCR2b of this invention maps to chromosome 9 p13.1-13.3 and the GPCR2B the nucleic acid sequence of this invention has 585 of 883 bases (66%) identical to a gb:GENBANK-ID:AR009514|acc:AR009514.1 mRNA from Unknown. (Sequence 1 from patent U.S. Pat. No. 5756309) (E=1.1e⁻⁶⁶).

[0075] The disclosed GPCR2b polypeptide (SEQ ID NO: 10) encoded protein having 314 amino acid residues is presented in Table 2D using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR2b has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6400. In other embodiments, it is localized at the Golgi body with a certainty of 0.4600, at the endoplasmic reticulum (membrane) with a certainty of 0.3700 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR2b peptide is between amino acids 49 and 50, at: NCT-IL. TABLE 2D Encoded GPCR2b protein sequence (SEQ ID NO:10) MTLGSLGNSSSSVSATFLLSGIPGLERMHIWISIPLCFMYLVSIPGNCTILFIIKTERSLHEPMYLFLSMLALIDLG LSLCTLPTVLGIFNVGARQISHDACFAQLFFIHCFSFLESSVLLSMAFDRFVAICHPLHYVSILTNTVIGRIGLVSL GTSVALIFPLPFMLKRFPYCGSPVLSHSYCLHQEVMKLACADMKANSIYGMFVIVSTVGIDSLLILFSYALILRTVL SIASRABRFKALNTCVSHICAVLLFYTPNIGLSVIHRFGKQAPHLVQVVMGFMYLLFPPVMNPIVYSVKTKQIRDRV THAFCY

[0076] The disclosed GPCR2b amino acid sequence of the protein of the invention was found to have 170 of 305 amino acid residues (55%) identical to, and 219 of 305 amino acid residues (71%) similar to, the 320 amino acid residue ptnr:SPTREMBL-ACC:O88628 protein from Rattus norvegicus (Rat) (PUTATIVE G-PROTEIN COUPLED RECEPTOR RA1C) (E=7.7e⁻⁹²).

[0077] Possible SNPs found for GPCR2b are listed in Tables 2E and 2F. TABLE 2E SNPs Consensus Base Position Depth Change PAF 313 21 C > G 0.429 543 28 T > — 0.071

[0078] TABLE 2F SNPs Amino Nucleotide Base Acid Base Position Change Position Change 124 A > G Silent N/A 145 T > C Silent N/A 789 A > G 257 Tyr > Cys 841 C > T Silent N/A

[0079] GPCR2 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypithalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putament, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0080] The term GPCR2 is used to refer to all GPCR2 variants or members of the GPCR2 family disclosed herein unless we identify a specific family member or variant.

[0081] Nucleotide sequence homologies between the GPCR2 variants is shown in a Clustal W in Table 2G.

[0082] Amino acid sequence homologies between the GPCR2 variants is shown in a Clustal W in Table 2H.

[0083] The amino acid sequence of GPCR2a has high homology to other proteins as shown in Table 2I. TABLE 2I BLASTX results for GPCR2a Smallest Sum High Prob Sequences producing High-scoring Segment Pairs: Reading Score P (N) ptnr:SPTREMBL-ACC:088628 GPCRECP - Rattus norv, 320 aa . . . 920 3.7e−92

[0084] The disclosed GPCR2a has homology to the amino acid sequences shown in the BLASTP data listed in Table 2J. TABLE 2J BLASTP results for GPCR2a Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi 13540539 ref NP_1104 prostate specific G- 320 172/305 224/305 2e−85 01.1 protein coupled (56%) (73%) receptor [Homo sapiens] gi 17063576 gb AAL35109 prostate-specific G 320 173/305 220/305 4e−85 .1|AF378854 1 protein-coupled (56%) (71%) receptor RA1c [Mus musculus] gi 11908220 gb AAG41684 MOR 3′Beta4 319 179/306 225/306 9e−85 .1| [Mus musculus] (58%) (73%) gi 3420759 gb AAD12761. putative G-protein 320 171/305 219/305 2e−84 1 coupled receptor (56%) (71%) RA1c [Rattus norvegicus] gi 14423836 sp Q9H344 O OLFACTORY RECEPTOR 312 173/298 218/298 2e−83 XI2 HUMAN 51I2 (HOR5′BETA12) (58%) (73%)

[0085] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 2K.

[0086] The homologies shown above are shared by GPCR2a and GPCR2b insofar as GPCR2a and GPCR2b are homologous as shown in Table 2H.

[0087] Table 2L lists the domain description from DOMAIN analysis results against GPCR2a. This indicates that the GPCR2a sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 2L Domain Analysis of GPCR2a gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:46) Length = 254 residues, 100% aligned Score = 70.9 bites (172), Expect = 1e−13 GPCR2a: 46 GNCTILFIIKTERSLHEPMYLFLSMLALIDLGLSLCTLPTVLGIFWVGAREISHDACGAQ 105 ||  ++ +|   + |  |  +||  ||+ ||   |   |  |     |        | Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR2a: 106 LFFIHCFSFLESSVLLSMAFDRFVAICHPLHYVSILTNTVIGRIGLVSLGRSVALIFPLP 165         +    +| +++ ||++|| ||| |  | |      + |+    ++ |  | Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR2a: 166 FM--LKRFPYCGSPVLSHSYCLHQEVMKLACADMKANSIYGMFVIVSTVGIDSLLILFSY 223     |+      + |    +                   | +   +    +  |+||  | Gnl|Pfam|pfam00001: 121 LFSWLRTVEEGNTTVCLIDFPEE-----------SYKRSYVLLSTLVGFVLPLLVILVCY 169 GPCR2a: 224 ALILRTVLSIASRAERF--------KALNTCVSHICAVLLFYTPMIGLSVIHRFGKQAPH 275   ||||+   |              ||    +  +   +| + |   + ++      + Gnl|Pfam|pfam00001: 170 TRILRTLRKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIW 229 GPCR2a: 276 LVQVVMGFMYLLFP---PVMNPIVY 297  |      + |        +|||+| Gnl|Pfam|pfam00001: 230 PVLPTALLITLWLAYVNSCLNPIIY 254

[0088] The protein similarity information, expression pattern, and map location for the olfactory receptor-like protein and nucleic acid GPCR2 suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) Acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0089] The disclosed GPCR2 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR2 epitope is from about amino acids 170 to 180. In additional embodiments, a GPCR2 epitope is from about amino acids 185 to 190, from about amino acids 195 to 200, and from 280 to 315. The GPCR2 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0090] GPCR3

[0091] The disclosed GPCR3 nucleic acid of 1251 nucleotides (also referred to as GMAC024428_A_) is shown in Table 3. The disclosed GPCR3 open reading frame begins with a ATG at nucleotides 91-93 and ending with a TGA codon at nucleotides 1162-1164. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 3A GPCR3 nucleotide sequence. (SEQ ID NO:11) CAAAATGATTATAGCTGACAAATCAGGAAGTGTGTTGTTAACTTCCTGACTTCTTATATTTCAGAGAACGAAGAGT TGAACCATTTAA ATGAATTGGGTAAATAAGAGTGTCCCACAGGAGTTCATTCTGTTAGTTTTCTCAGATCAACCAT GGCTAGAATTCCACCCTTTGTGATGTTTCTGTTTTCCTATATCTTGACAATCTTTGGCAATCTGACAATAATTCTT GTGTCACATGTGGATTCAAACTCCACACCCCTATGTACTTTTTTCTTAGCAATCTCTCACTCCTGGACCTTTGCTA TACCACAAGTACAGTTCCACAAATGCTGGTAAACATATGCAACACCAGGAAAGTAATCAGTTATGGTGGCTGTGTGG CCCAGCTTTTCATTTTCCTGGCCTTGGGTTCCACAGAATGTCTTCTCCTGGCCGTCATGTGCTTTGATAGGTTGTA GCTATTTGTCGGCCTCTCCATTACTCAATTATCATGCACCAGAGGCTCTGCTTCCAGTTGGCAGCTGCATCCTGGAT TAGTGGCTTTAGCAATTCAGTATTACAGTCCACCTGGACACTTAAGATGCCACTGTGTGGTCACAAAGAAGTGGATC ACTTCTTCTGTGAAGTCCCTGCTCTGCTCAAGTTGTCCTGTGTTGACACAACAGCAAATGAGGCTGAACTATTCTTC ATCAGTGTGCTATTCCTTCTAATACCCGTGACACTCATCCTTATATCGTATGCTTTTATTGTCCAAGCAGTGTTGAG AATCCAGTCTGCTGAAGGTCAACGAAAGGCATTTGGGACATGTGGCTCCCATCTAATTGTCGTGTCACTTTTTTATG GTACAGCTATCTCCATGTACCTGCAACCACCTTCACCCAGCTCCAAAGACCGGGGAAAGATGGTTTCTCTCTTCTGT GGAATCATTGCACCCATGCTGAATCCCCTTATATATACACTTAGGAACAAAGAGGTAAAGGAAGCCTTTAAAAGGTT GGTTGCAAAGAGTCTTCTTAATCAAGAAATAAGAAATATGCAAATGATAAGCTTTGCTAAAGACACAGTGCTTACTT ACCTTACTAACTTCTCCGCAAGTTGTCCTATTTTTGTCATTACTATAGAAAACTATTGTAATCTCCCTCAAAGAAAA TTTCCTTGA CAAAAAGCTATATTTGTTTCTGTTGCCTAAACATTTTCATTGAACAAGCCCCCAGAATTGGCCTTCCA ATGCACCAAAAACTGTAAT

[0092] The disclosed GPCR3 of this invention maps to chromosome 3 the nucleic acid sequence of this invention has 881 of 1119 bases (78%) identical to a gb:GENBANK-ID:RATOL1RECE|acc:L34074.1 mRNA from Rattus norvegicus (Rat OL1 receptor gene, complete cds (E=2.1e⁻¹⁴²). Chromosome localization information was assigned using OMIM, the electronic northern bioinformatic tool implemented by CuraGen Corporation, public ESTs, public literature references and/or genomic clone homologies. This was executed to derive the chromosomal mapping of the SeqCalling assemblies, Genomic clones, literature references and/or EST sequences that were included in the invention.

[0093] The disclosed GPCR3 polypeptide (SEQ ID NO: 12) encoded protein having 357 amino acid residues is presented in Table 3B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR3 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the microbody (peroxisome) with a certainty of 0.3000. The most likely cleavage site for a GPCR3 peptide is between amino acids 41 and 42, at: IFG-NL. TABLE 3B Encoded GPCR3 protein sequence. (SEQ ID NO:12) MNWVNKSVPQEFILLVFSDQPWLEIPPFVMFLFSYILTIFGNLTIILVSHVDFKLHTPMYFFLSNLSLLDLCYTTST VPQMLVNICNTRKVISYGGVAQLFIFLALGFSTECLLLAVMCFDRFVAICRPLHYSIIMHQRLCFQLAAASWISGFS NSVIQSTWTLKMPLCGHKEVDEFFCEVPALLKLSCVDTTANEAELFFISVLFLLIPVTLILISYAFIVQAVLRIQSA EGQRKAFGTCGSHLIVVSLFYGTAISMYLQPPSPSSKDRGKMVSLFCGIIAPMLNPLIYTLRNKEVKFAFK2LVAKS LLNQEIRNMQMISFAlGJTVLTYLTNFSASCPIFVITIENYCNLPQRKFP

[0094] The disclosed GPCR3 full amino acid sequence of the protein of the invention was found to have 310 of 310 amino acid residues (100%) identical to, and 310 of 310 amino acid residues (100%) similar to, the 310 amino acid residue ptnr:SPTREMBL-ACC:Q9Y299 protein from Homo sapiens (Human) (OLFACTORY RECEPTOR (E=8.6e⁻¹⁶⁵).

[0095] GPCR3 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0096] Possible SNPs found for GPCR3 are listed in Tables 3C and 3D. The SNP at bp 1122 found in Table 3D is also referred to as Accession Number CG92194-01. TABLE 3C SNPs Consensus Base Position Depth Change PAF 124 12 A > C 0.167 319 11 A > G 0.273

[0097] TABLE 3D SNPs Nucleotide Base Amino Base Position Change Acid Change Position 129 T > C Silent N/A 318 T > C Silent N/A 1122 T > C Silent N/A

[0098] The amino acid sequence of GPCR3 has high homology to other proteins as shown in Table 3E. TABLE 3E BLASTX results for GPCR3 Smallest Sum High Prob Sequences producing High-scoring Segment Pairs: Reading Score P (N) ptnr:SPTREMBL-ACC:Q9Y299 OLF RECP - Homo Sapiens, 310 aa . . . 1605 8.6e−165

[0099] The disclosed GPCR3 has homology to the amino acid sequences shown in the BLASTP data listed in Table 3F. TABLE 3F BLASTP results for GPCR3 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|15304846|ref XP_05 olfactory 357 357/357 357/357 0.0 3609.1 receptor, family (100%)  (100%)  2, subfamily B, member 2 [Homo sapiens] gi|14780900|ref NP_14 olfactory 357 356/357 357/357 0.0 9046.1 receptor, family (99%) (99%) 2, subfamily B, member 2 [Homo sapiens] gi|3080467 emb|CAB114 olfactory 310 310/310 310/310 e−159 27.1 receptor (100%)  (100%)  [Homo sapiens] gi|11177906|ref NP_06 Olfactory 313 261/310 284/310 e−134 8632.1 receptor (84%) (91%) [Rattus norvegicus] gi 14423785 sp P58173 O OLFACTORY RECEPTOR 313 253/310 278/310 e−128 236 HUMAN 2B6 (HS6M1-32) (81%) (89%) (OLFACTORY RECEPTOR 6-31) (OR6-31)

[0100] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 3G.

[0101] Table 3H lists the domain description from DOMAIN analysis results against GPCR3. This indicates that the GPCR3asequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 3H Domain Analysis of GPCR3 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:52) Length = 254 residues, 94.5% aligned Score = 110 bits (275), Expect = 1e−25 GPCR3a: 41 GNLTIILVSHVDFKLHTPMYFFLSNLSLLDLCYTTSTVPQMLVNICNTRKVISYGGCVAQ 100 ||| +|||     || ||   || ||++ || +  +  |  |  +     |     | Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR3a: 101 LFIFLALGSTECLLLAVMCFDRFVAICRPLHYSIIMHQRLCFQLAAASWISGFSNSVLQS 160   +|+  |    |||  +  ||++||  || |  |   |    |    |+     |+ Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR3a: 161 T--WTLKMPLCGHKEVDHFFCEVPALLKLSCVDTTANEAELFFISVLFLLIPVTLILISY 218    |   +           | |                  +   +++  ++|+ +||+ | Gnl|Pfam|fam00001: 121 LFSWLRTVEEGNTTVCLIDFPEESVKRSY-----------VLLSTLVGFVLPLLVILVCY CPCR3a: 219 AFIV---------QAVLRIQSAEGQRKAFGTCGSHLIVVSLFYGTAISMYL----QPPSP 265   |+         |  |+ +|+  ++ |       ++ |  +    | + | Gnl|Pfam|pfam00001: 170 TRILRTLRKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIW 229 GPCR3a: 266 SSKDRGKMVSLFCGIIAPMLNPLIY 290        +++|+   +   |||+|| Gnl|Pfam|pfam00001: 230 RVLPTALLITLWLAYVNSCLNPIIY 254

[0102] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR3 protein and nucleic acid disclosed herein suggest that GPCR3 may have important structural and/or physiological functions characteristic of the GPCR family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0103] The disclosed GPCR3 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR3 epitope is from about amino acids 140 to 160. In additional embodiments, a GPCR3 epitope is from about amino acids 235 to 245, from about amino acids 260 to 275, from 295 to 310, from 320 to 325 and from 330 to 335. The GPCR3 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0104] GPCR4

[0105] The disclosed GPCR4 nucleic acid of 953 nucleotides (also referred to as CG50169-01) is shown in Table 4A. The disclosed GPCR4 open reading frame (“ORF”) begins with a ATG at nucleotides 16-18 and ending with a TAA codon at nucleotides 946-948. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 4A GPCR4 nucleotide sequence. (SEQ ID NO:13) GCCTGACCAAAAAGA ATGGCAGCCAAAAACTCTTCTGTGACAGAGTTTATCCTCGAAGGCTTAACCCACCAGCCGGG ACTGCGGATCCCCCTCTTCTTCCTGTTTCTGGGTTTCTACACGGTCACCGTGGTGGGGAACCTGGGCTTGATAACCC TGATTGGGCTGAACTCTCACCTGCACACTCCCATGTACTTCTTCCTTTTTAACCTCTCTTTAATAGATTTCTGTTTC TCCACTACCATCACTCCCAAAATGCTGATGAGTTTTGTCTCAAGGAAGAACATCATTTCCTTCACAGGGTGTATGAC TCAGCTCTTCTTCTTCTGCTTCTTTGTCGTCTCTGAGTCCTTCATCCTGTCAGCGATGGCGTATGACCGCTACGTGG CCATCTGTAACCCACTGTTGTACACAGTCACCATGTCTTGCCAGGTGTGTTTGCTCCTTTTGTTGGGTGCCTATGGG ATGGGGTTTGCTGGGGCCATGGCCCACACAGGAAGCATAATGAACCTGACCTTCTGTGCTGACAACCTTGTCAATCA TTTCATGTGTGACATCCTTCCTCTCCTTGAGCTCTCCTGCAACAGCTCTTACATGAATGAGCCGGTGGTCTTTATTG TGGTGGCTGTTGACGTTGGAATGCCCATTGTCACTGTCTTTATTTCTTATGCCCTCATCCTCTCCAGCATTCTACAC TTCTGGTGCTTTCATGTATCTCAAACCCCTTTCCATCCTGCCCCTCGAGCAAGGGAAAGTGTCCTCCCTGTTCTATA CCATAATAGTCCCCCGTGTTAAACCCATTAATCTATAGCTTGAGGAACAAGGATGTCAAAGTTGCCCTGAGAGAACT TTGGGCAGAAAAAATCTTTTCTTAA GAAAG

[0106] The GPCR4 the nucleic acid sequence of this invention has 527 of 660 bases (79%) identical to a gb:GENBANK-ID:SCO233799|acc:AJ233799.1 mRNA from Stenella coeruleoalba (Stenella coeruleoalba olfactory receptor pseudogene, partial, clone SCor3) (E=7.5e⁻⁸⁹).

[0107] The disclosed GPCR4 polypeptide (SEQ ID NO: 14) encoded protein having 310 amino acid residues is presented in Table 4B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR4 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the microbody (peroxisome) with a certainty of 0.3000. The most likely cleavage site for a GPCR4 peptide is between amino acids 40 and 41, at: VVG-NL. TABLE 4B Encoded GPCR4 protein seqnence. (SEQ ID NO:14) MAAKNSSVTEFILEGLTHQPGLRIPLEFFLFLGFYTVTVVGNLGLITLIGLNSHLHTPMYFFLFNLSLIDFCFSTTIT PKMLMSFVSRKNIISFTGCMTQLFFFCFFVVSESFILSAMAYDRYVAICNPLLYTVTMSCQVCLLLLLLGAYGMGFAG AAMAHTGSIMNLTFCADNLVNHFMCDILPLLELSCNSSYNMEPVVFIVVAVDVGMPIVTVFISYALILSSILHNSSTE GGRSKAFSTCSSHIIVVSLFFGSGAFMYLKPLSILPLEQGKVSSLFYTIIVPVLNPLIYSLRNKDVKVALRRTLGRKI FS

[0108] The disclosed GPCR4 amino acid sequence of the protein of the invention was found to have 255 of 304 amino acid residues (83%) identical to, and 282 of 304 amino acid residues (92%) similar to, the 304 amino acid residue ptnr:SPTREMBL-ACC:Q9QW36 protein from Rattus sp (OR14=ODORANT RECEPTOR) (E=3.2e⁻¹³⁴).

[0109] GPCR4 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0110] The amino acid sequence of GPCR4 has high homology to other proteins as shown in TABLE 4C BLASTX results for GPCR4 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Reading Score P(N) ptnr:SPTREMBL-ACC:QPQW36 ODOR 304 aa. 1317 3.2e−134 RECP - Rattus sp,

[0111] The disclosed GPCR4 has homology to the amino acid sequences shown in the BLASTP data listed in Table 4D. TABLE 4D BLASTP results for GPCR4 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|11692541|gb|AAG398 odorant receptor 310 256/310 283/310 e−120 67.1|AF282282_1 K23 [Mus musculus] (82%) (90%) Length = 310 gi|11692535|gb|AAG398 odorant receptor 310 259/310 283/310 e−117 64.1|AF282279_1 K21 [Mus musculus] (83%) (90%) gi|11692539|gb|AAG398 odorant receptor 309 258/310 284/310 e−117 66.1|AF282281_1 K22 [Mus musculus] (83%) (91%) gi|423701|pir |S29709 olfactory 304 255/304 282/304 e−117 receptor OR14 - (83%) (91%) rat gi|14423794|sp|Q15620 OLFACTORY 311 248/311 276/311 e−110 O8B8_HUMAN RECEPTOR 8B8 (79%) (88%) (OLFACTORY RECEPTOR TPCR85)

[0112] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 4E.

[0113] Table 4F lists the domain description from DOMAIN analysis results against GPCR4. This indicates that the GPCR4 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 4F Domain Analysis of GPCR4 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodospin family). (SEQ ID NO:58) Length = 254 residues, 94.9% aligned Score = 62.0 bits (149), Expect = 5e−11 GPCR4: 53 HLHTPMYFFLFNLSLIDFCFSTTITPKMLMSFVSRKNIISFTGCMTQLFFFCFFVVSESF 112  | ||   || ||++ |  |  |+ |  |   |    +     |      |     + Gnl|Pfam|pfam00001: 14 KLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLVGALFVVNGYASIL 73 GPCR4: 113 ILSAMAYDRYVAICNPLLYTVTMSCQVCLLLLLGAYGMGFAGAMAHTGSIMNLTFCADNL 172 +|+|++ |||+|| +|| |    + +   +|+|  + +    ++     ++ Gnl|Pfam|pfam00001: 74 LLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPP---LLFSWLRTVEE 130 GPCR4: 173 VNHFMCDILPLLELSCNSSYMNEPVVFIVVAVDVGMPIVTVFISYALIL---------SS 223  |  +| |    |    |  +   +|  |+      |++ + + |  || Gnl|Pfam|pfam00001: 131 GNTTVCLIDFPEESVKRSYVLLSTLVGFVL------PLLVILVCYTRILRTLRKRARSQR 184 GPCR4: 224 ILHNSSTEGRSKAFSTCSSHIIVVSLFFGSGAFMYLKPLSILP----LEQGKVSSLFYTI 279  |   |+  |  |       ++ |  +      + |  | +|     |    + +|+ Gnl|Pfam|pfam00001: 185 SLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITLWLAY 244 GPCR4: 280 IVPVLNPLIY 289 +   |||+|| Gnl|Pfam|pfam00001: 245 VNSCLNPIIY 254

[0114] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR 4 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of appetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) Acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0115] The disclosed GPCR4 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR4 epitope is from about amino acids 220 to 240. In additional embodiments, a GPCR4 epitope is from about amino acids 280 to 310. The GPCR4 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0116] GPCR5

[0117] The disclosed GPCR5 nucleic acid of 1103 nucleotides (also referred to as AC009758_da1) is shown in Table 5A. The disclosed GPCR5 open reading frame (“ORF”) begins with a ATG at nucleotides 66-68 which encodes a serine (the first amino acid of the mature protein) and ending with a TAA codon at nucleotides 1020-1022. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 5A GPCRS nucleotide sequence. (SEQ ID NO:15) TGCAGATTTTATCTTCTTTCTACCTCTGTGAGTAGAAGGTGAGGTTCTGANAGTTCTCCCCAGCT ATGCCTACTGTA AACCACAGTGGCACTAGCCACACAGTCTTCCACTTGCTGGGCATCCCTGGCCTACAGGACCAGCACATGTGGATTTC TATCCCATTCTTCATTTCCTATGTCACCGCCCTTCTTGGGAACAGCCTGCTCATCTTCATTATCCTCACAAAGCGCA GCCTCCATGAACCCATGTACCTCTTCCTCTGCATGCTGGCTGGAGCAGACATTGTCCTCTCCACGTGCACCATTCCT CAGCCCTTAGCTATCTTCTGGTTCCGTGCTGGGGACATCTCCCTGGATCGTTGCATCACTCAGCTCTTCTTCATCCA TTCCACCTTCATCTCTGAGTCAGGGATCTTGCTGGTGATGGCCTTTGACCACTATATTGCCATATGCTACCCACTGA GGTACACCACCATTCTTACAAATGCTCTGATCAAGAAAATTTGTGTGACTGTCTCTCTGAGAAGTTATGGTACAATT TTCCCTATCATATTTCTTTTAAAAAGATTGACTTTCTGCCAGAATAATATTATTCCACACACCTTTTGTGAACACAT TGGCCTAGCCAAATATGCATGTAATGACATTCGAATAAACATTTGGTATGGGTTTTCCATTCTAATGTCGACGGTCC TCTTAAATGTTGTACTAATTTTTATTTCCTATATGCTGATTCTCCATGCTGTCTTCCACATACCTTCTCCAGATGCT TGCCACAAAGCTCTCAACACATTTGGCTCCCATGTCTGCATCATCATCCTCTTTTATGGGTCTGGCATCTTCACAAT CCTTACCCAGAGGTTTGGACGCCACATTCCACCTTGTATCCACATCCCGTTGGCTAATGTCTGCATTCTGGCTCCAC CTATGCTGAATCCCATTATTTATGGGATCAAAACCAAGCAAATCCAGGAACAGGTGGTTCAGTTTTTGTTTATAAAA CAGAAAATAACTTTGGTTTAA GAACTGAGTTTTCAGAATCTCTAGCTATCTGGTAAGTGGGTATGAAAGTGGTAGAT GGGAGAGGTCAGCTGATACCGTAGA

[0118] The disclosed GPCR5 of this invention maps to chromosome 11 and the GPCR5 the nucleic acid sequence of this invention has 687 of 1030 bases (66%) identical to a gb:GENBANK-ID:AF121975|acc:AF121975.1 mRNA from Mus musculus (Mus musculus odorant receptor S18 gene, complete cds) (E=6.7e⁻⁷⁴). Chromosome localization information was assigned using OMIM, the electronic northern bioinformatic tool implemented by CuraGen Corporation, public ESTs, public literature references and/or genomic clone homologies. This was executed to derive the chromosomal mapping of the SeqCalling assemblies, Genomic clones, literature references and/or EST sequences that were included in the invention.

[0119] The disclosed GPCR5 polypeptide (SEQ ID NO: 16) encoded protein having 318 amino acid residues is presented in Table 5B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR5 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the mitochondrial inner membrane with a certainty of 0.3000. The most likely cleavage site for a GPCR5 peptide is between amino acids 53 and 54, at: ILT-KR. TABLE 5B Encoded GPCR5 protein sequence. (SEQ ID NO:16) MPTVNESGTSETVFHLLGIPGLQDQHMWISIPFFISYVTALLGNSLLIFIILTKRSLNEPNYLFLCMLAGADIVLST CTIPQALAIFWFRAGDISLDRCITQLFFIHSTFISESGILLVMAFDHYIAICYPLRYTTILTNALIKKICVTVSLRS YGTIFPIIFLLKRLTFCQNNIIPHTFCEHIGLAKYACNDIRINIWYGFSILMSTVVLDVVLIFISYMLILHAVFHMP SPDACHKALNTFGSHVCIIILFYGSGIFTILTQRFGRHIPPCIHIPLANVCILAPPMLNPIIYGIKTKQIQEQVVQF LFIKQKITLV

[0120] The disclosed GPCR5 amino acid sequence of the protein of the invention was found to have 184 of 303 amino acid residues (60%) identical to, and 237 of 303 amino acid residues (78%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9WU89 protein from Mus musculus (Mouse) (ODORANT RECEPTOR S18) (E=1.8e⁻¹⁰¹).

[0121] GPCR5 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0122] The amino acid sequence of GPCR5 has high homology to other proteins as shown in Table 5C. TABLE 5C BLASTX results for GPCR5 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Reading Score P (N) Ptnr:SPTREMBL-ACC:Q9WU89 321 aa . . . 1008 1.8e−101 ODOR RECP - Mus musculus,

[0123] The disclosed GPCR5 has homology to the amino acid sequences shown in the BLASTP data listed in Table 5D. TABLE 5D BLASTP results for GPCR5 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|9938014 ref|NP_064 odorant receptor 321 184/303 237/303 6e−93 686.1| S18 gene (60%) (77%) [Mus musculus] gi|7305349|ref|NP_038 MOR 3′Beta1 326 168/307 227/307 2e−79 647.1| [Mus musculus] (54%) (73%) gi|6532001|gb AAD2759 odorant receptor 339 149/293 214/293 6e−75 6.2 AF121976_1 S19 [Mus musculus] (50%) (72%) gi|14423837|sp|Q9H346 OLFACTORY 318 153/299 212/299 9e−74 |OYD1_HUMAN RECEPTOR 52D1 (51%) (70%) (HOR5′BETA14) gi|9935442|ref|NP_064 odorant receptor 318 154/305 212/305 4e−69 688.1| S46 gene (50%) (69%) [Mus musculus]

[0124] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 5E.

[0125] Table 5F lists the domain description from DOMAIN analysis results against GPCR2a. This indicates that the GPCR2a sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 5F Domain Analysis of GPCR5 gnl|Pfam|pfam0001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO: 64) Length = 254 residues, 100.0% aligned Score = 87.4 bits (215), Expect = 1e−18 GPCRS: 43 GNSLLIFTILTKRSLHEPMYLBLCMLAGADIVLSTCTIPQALAIFWF2AODISLDRCITQ 102 || |+| +||+ + |  |  +||  || ||++      | |             | Gnl|Pfam|pfam0001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR5: 103 LFFIHSTFISESGILLVMAFDHYTAICYPLRYFTILTNALIKKICVTVSLRSYGTIFPII 162           +   +|  ++ | |+|| +||||  | |    | + + | + +     | + Gnl|pFAM|PFAM0001: 61 GALFVVNOYASILLLTAISIDRYLAIVUPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR5: 163 FLLKRLTFCQNNIIPHTFCEHIGLAKYACNDIRINIWYGFSILMSTVVLDVVLIFISYML 222       |  + |             | +   +   + +   +|+  |    +|+ + Gnl|Pfamp|fam0001: 121 LFSWLRTVEEGNTTVCLIFFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRA 180 GPCR5: 223 ILHAVFHNPSPDACHKALNTFGSHVCIITLFYGSGIFTILTQRFOREIPPCIHIP--LAN 280          |      |       |  ++ +    |  +|       |   +     + Gnl|Pfam|pfam0001: 181 RSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITL 240 GPCR5: 281 VCILAPPMLNPIIY 294         |||||| Gnl|Pfam|pfam0001: 241 WLAYVNSCLNPIIY 254

[0126] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR5 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders; control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0127] The disclosed GPCR5 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR5 epitope is from about 170 to 175 amino acids. In additional embodiments, a GPCR5 epitope is from about amino acids 180 to 185, from about amino acids 190 to 192, from about amino acids 195 to 198, from 240 to 245, from about 290 to 295, from 298 to 300 and from 310 to 320. The GPCR5 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0128] GPCR6

[0129] The disclosed GPCR6 nucleic acid of 972 nucleotides (also referred to as CG50149-01) is shown in Table 6A. The disclosed GPCR6 open reading frame (“ORF”) begins with a ATG at nucleotides 18-20 and ending with a TGA codon at nucleotides 963-965. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 6A GPCR6 nucleotide sequence. (SEQ ID NO:17) AAACTTGGACGATCGACATQGAAATTGTCTCCACAGGAAACGAAACTATTACTGAATTTGTCCTCCTTGGCTTCTAT GACATCCCTGAACTGCATTTCTTGTTTTTTATTGTATTCACTGCTGTCTATGTCTTCATCATCATAGCGAATATGCT GATTATTGTAGCAGTGGTTAGCTCCCAGAGGCTCCACAAACCCATGTATATTTTCTTGGCGAATCTGTCCTTCCTGG ATATTCTCTACACCTCCGCAGTGATGCCAAAAATGCTGGAGGGCTTCCTGCAAGAAGCAACTATCTCTGTGGCTGGT TGCTTGCTCCAGTTCTTTATCTTCQGCTCTCTAGCCACAGCTGAATGCTTACTGCTGGCTGTCATGGCATATGACCG CTACCTGGCAATTTGCTACCCACTCCACTACCCACTCCTGATGGGGCCCAGACGGTACATGGGGCTGGTGGTCACAA CCTGGCTCTCTGGATITGTGGTAGATGGACTGGTTGTGGCCCTGGTGGCCCAGCTGACGTTCTGTGGCCCCAACCAC ATTGACCAGTTTTACTGTGACTTTATGCTTTTCGTGGGCCTGGCTTGCTCGGATCCCAGAGTGGCTCAGGTGACAAC TCTCATTCTGTCTGTGTTCTGCCTCACTATTCCTTTTGGACTGATTCTGACATCTTATGCCAGAATTGTGGTGGCAG TGCTGAGAGTTCCTGCTGGGGCAAGCAAGAGAAGGGCTTTCTCCACATGCTCCTCCCACCTAGCTGTAGTGACCACA TTCTATGGAACGCTCATGATCTTTTATGTTGCACCCTCTGCTGTCCATTCCCAGCTCCTCTCCAAGGTCTTCTCCCT GCTCTACACTGTGGTCACCCCTCTCTTCAATCCTGTGATCTATACCATGAGGAACAAGGAGGTGCATCAGGCACTTC GGAAGATTCTCTGTATCAAACAAACTGAAACACTTGATTGAAGGAGAG

[0130] The GPCR6 the nucleic acid sequence of this invention has 595 of 707 bases (84%) identical to a gb:GENBANK-ID:AF044038|acc:AF044038.1 mRNA from Marmota marmota (Marmota marmota clone AMOR 6 olfactory receptor mRNA, partial cds) (E=5.0e⁻¹⁰⁸).

[0131] The disclosed GPCR6 polypeptide (SEQ ID NO: 18) encoded protein having 315 amino acid residues is presented in Table 6B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR6 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the microbody (peroxisome) with a certainty of 0.3000. The most likely cleavage site for a GPCR6 peptide is between amino acids 54 and 55, at: VSS-QR. TABLE 6B Encoded GPCR6 protein sequence (SEQ ID NO:18) MEIVSTGNETITEFVLLGFYDIPELHFLFFIVFTAVYVFIIIGNMLIIVAVVSSQRLHKPMYIFLANLSFLDILYTS AVMPKMLEGFLQEATISVAGCLLQFFIFGSLATAECLLLAVMAYDRYLAICYPLHYPLLMGPRRYMGLVVTTWLSGF VVDGLVVALVAQLRFCGPNHIDQFYCDFMLFVGLACSDPRVAQVTTLILSVFCLTIPFGLILTSYARIVVAVLRVPA GASRRRAFSTCSSHLAVVTTFYGTLMIFYVAPSAVHSQLLSKVFSLLYTVVTPLFNPVIYTMRNKEVHQALRKILCI KQTETLD

[0132] The disclosed GPCR6 amino acid sequence of the protein of the invention was found to have 140 of 297 amino acid residues (47%) identical to, and 188 of 297 amino acid residues (63%) similar to, the 324 amino acid residue ptnr:SPTREMBL-ACC:Q9WU86 protein from Mus musculus (Mouse) (ODORANT RECEPTOR S1) (E=1.2e⁻⁶⁸).

[0133] GPCR6 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0134] Possible SNPs found for GPCR6 are listed in Tables 6C. TABLE 6C SNPs Amino Nucleotide Base Acid Base Position Change Position Change 376 C > T 120 Ala > Val 810 G > A 265 Ala > Thr

[0135] The amino acid sequence of GPCR6 has high homology to other proteins as shown in Table 6D. TABLE 6D BLASTX results for GPCR6 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Reading Score P (N) Ptnr:SPTREMBL-ACC:Q9WU86 ODOR 324 aa. 698 1.2e−68 RECP S1 - Mus musculus,

[0136] The disclosed GPCR6 has homology to the amino acid sequences shown in the BLASTP data listed Table 6E. TABLE 6E BLASTP results for GPCR6 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|7363441|ref|NP_039 olfactory 315 315/315 315/315  e−148 225.1| receptor, family (100%) (100%) 11, subfamily A, member 1 [Homo sapiens] gi|12054471|emb CAC20 olfactory 315 314/315 314/315  e−147 543.1| receptor (99%) (99%) [Homo sapiens] gi|5901488 gb AAD5530 olfactory 236 194/236 210/236 1e−88 9.1 AFC44038_1 receptor (82%) (88%) [Marmota marmota] gi|7242165|ref|NP_035 olfactory 327 133/305 191/305 1e−61 113.1| receptor 41 (43%) (62%) [Mus musculus] gi|13928994|ref NP_11 olfactory 327 133/307 194/307 6e−61 3898.1 receptor 41 (43%) (62%) [Rattus norvegicus]

[0137] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 6F.

[0138] Table 6G lists the domain description from DOMAIN analysis results against GPCR6. This indicates that the GPCR6 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 6G Domain Analysis of GPCR6 gnl|Pfam|pfam0001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO: 70) Length = 254 residues, 100.0% aligned Score = 99.8 bits (247), Expect = 2e−22 GPCR6: 43 GNMLIIVAVVSSQRLHKPMYIFLANLSFLDILYTSAVMPKMLEGFLQEA-TISVAGCLLQ 101 ||+|+|+ ++ +++|  |  ||| ||+  |+|+   + | |   +        | | | Gnl|Pfam|pfam0001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDNVFGOALCKLV 60 GPCR6: 102 FFIFGSLATAECLLLAVMAYDRYLAICYPLHYPLLMGPRRYMGLVVTTWLSGFVVDGLVV 161   +|     |  |||  ++ |||||| +|| |  +  |||    |++  |+    +    + Gnl|Pfam|pfam0001 61 GALFVVNGYASILLLTAISIDRYLAIVEPLRYRRIRTPRRAKVLILLVNVLALLLSLPPL 120 GPCR6: 162 ALVAQLRFCGPNHIDQFYCDFMLFVGLACSDPRVAQVTTLILSVFCLTIPFGLILTSYAR 221            |      |           +  | +   |+ ++    +|  +||  | | Gnl|Pfam|pfam00001: 121 LFSWLRTVEEGN---TTVCLIDF------PEESVKRSYVLLSTLVGFVLPLLVILVCYTR 171 GPCR6: 222 IVVAVLRV---------PAGASRRRAFSTCSSHLAVVTTFYGTLMIFYVAP----SAVHS 268 |+  + +           + + |+ |      +  |   +     ++  +      | Gnl|Pfam|pfam00001: 172 ILRTLRKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRV 231 GPCR6: 269 QLLSKVFSLLYTVVTPLFNPVIY 291    + + +|     |    ||+|| Gnl|Pfam|pfam00001: 232 LPTALLITLWLAYVNSCLNPIIY 254

[0139] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR6 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0140] The disclosed GPCR6 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR6 epitope is from about amino acids 160 to 165. In additional embodiments, a GPCR6 epitope is from about amino acids 230 to 235, from about amino acids 285 to 295, and from 305 to 310. The GPCR6 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0141] GPCR7

[0142] The disclosed GPCR7 nucleic acid of 1383 nucleotides (also referred to as GM_(—)33202597_A_da1) is shown in Table 7A. The disclosed GPCR7 open reading frame (“ORF”) begins with a ATG at nucleotides 6-8 and ending with a TGA codon at nucleotides 939-941. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 7A GPCR7 nucleotide sequence. (SEQ ID NO: 19) TAGAAATGGAACGACCACAAAGTGATTTTAACCAAACTGAAGTTGCTCAATTTTTCCTCATGGGATTTTCGAATTCC TGGGATATTCAGATTGTACATGCTGCTCTATTCTTCCTAGTTTACCTCGCAGCTGTCATAGGAAATCTCCTAATCAT CATACTTACCACTCTGGATGTTCACCTCCAAACCCCAATGTATTTCTTTTTGAGAAACTTGTCTTTCTTAGATTTTT GTTACATCTCTGTCACAATTCCAAAATCTATTGTTAGTTCCTTGACTCATGATACTTCCATTTCTTTCTTTGGGTGT GCTCTGCAAGCCTTCTTTTTCATGGACTTGGCAACTACQGAQGTAQCCATCCTTACAGTGATGTCCTATGACCGCTA TATGCCCATCTGCCGGCCTTTACATTATGAGGTCATCATAAACCAAGGTGTCTGTCTGACGATGATGGCCATGTCGT GGCTCAGTGGGGTGATCTGTCGATTCATGCATGTGATAGCAACATTCTCATTACCATTCTGTGGGCGCAATAGAATA CGTCAATTTTTCTGTAATATTCCACAGCTCCTAAGCCTCTTAGACCCCAAAGTAATTACCATTGAGATTGGAGTCAT GGTTTTTGGTACAAGTCTTGTGATAATCTCCTTTGTTGTAATTACTCTCTCCTACATGTACATTTTTTCTGTCATCA TGACGATTCCTTCTAAGGAGGGTAGATCAAAAACATTTTCTACCTGCATTCCACATCTTGTGGTTGTAACACTCTTT ATGATATCTGGCAGCATTGCCTATGTGAAGCCAATTTCAAATTCTCCCCCCGTTCTGGATGTTTTCCTGTCTGCGTT CTACACAGTCGTGCCCCCGACCCTGAACCCCGTCATCTATAGTCTGAGGAATAGGGACATGAAGGCAGCCCTGAGAA GGCAGTGTGGTCCCTGAGAAGGCAGTGTGGTATCCTAGATGAACAATTTGATTACGGACCAGACTCTTGAACTCTTG CTCTAATCAGGCAATTTQTAAACTCTCTGGGCTTATATTTTCAATTGATTGCTGAGCTCTTTCTTGATTTTTAAATT AAATTCACCTATAGTTTACCATACTAACCATATTTGGGTGAATTCAACCTTAGAATGCACTAAAAGGTACTTCGGGG TGTTCAAAACATTAGAACTTGTGCTTTTATTCATTTTTATGAGTTGTAGATCTCAAAATTTTATAAATTATATTGTA CTCAGTAATACAACATATTAATTAATATAAAAGTGAATTACTAATATAAATGAATTACTACCGTATGTGTATATTAA TTACAGCAGAACAAGATCATATGGATTAAAAACAACCAAATGGAAAATAAACATAAGGTAACAGTGTGTGCTCA

[0143] The disclosed GPCR7 of this invention maps to chromosome 1 the GPCR7 the nucleic acid sequence of this invention has 583 of 916 bases (63%) identical to a gb:GENBANK-ID:RATOLFPROQ|acc:M64391.1 mRNA from Rattus norvegicus (Rat olfactory protein mRNA, complete cds) (E=1.1e⁻⁴⁰). Chromosome localization information was assigned using OMIM, the electronic northern bioinformatic tool implemented by CuraGen Corporation, public ESTs, public literature references and/or genomic clone homologies. This was executed to derive the chromosomal mapping of the SeqCalling assemblies, Genomic clones, literature references and/or EST sequences that were included in the invention.

[0144] The disclosed GPCR7 polypeptide (SEQ ID NO: 20) encoded protein having 311 amino acid residues is presented in Table 7B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR7 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the mitochondrial inner membrane with a certainty of 0.0300. The most likely cleavage site for a GPCR7 peptide is between amino acids 59 and 60, at: VHL-QT. TABLE 7B Encoded GPCR7 protein sequence. (SEQ ID NO: 20) MERPQSDFNQTEVAEFFLMGFSNSWDIQIVHAALFFLVYLAAVIGNLLIIILTTLDVHLQTPMYFFLRNLSFLDFCY ISVTIPKSIVSSLTHDTSISFFGCALQAFFFMDLATTEVAILTVMSYDRYMAICRPLHYEVIINQGVCLRMMAMSWL SGVICGFMHVIATFSLPFCGRNRIRQFFCNIPQLLSLLDPKVITIETGVMVFGTSLVIISFVVITLSYMYIFSVIMR IPSKEGRSKTFSTCIPHLVVVTLFMISGSIAYVKPISNSPPVLDVFLSAFYTVVPPTLNPVIYSLRNRDMKAALRRQ CGP

[0145] The disclosed GPCR7 amino acid sequence of the protein of the invention was found to have 154 of 299 amino acid residues (51%) identical to, and 205 of 299 amino acid residues (68%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9UGF5 protein from Homo sapiens (Human) (BA150A6.4 (NOVEL 7 TRANSMEMBRANE RECEPTOR (RHODOPSIN FAMYLY) (OLFACTORY RECEPTOR LIKE) PROTEIN (HS6M1-28) (E=2.7e⁻⁸⁰).

[0146] GPCR7 disclosed in this invention is expressed in at least the following tissues: hematopoietic tissues. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources.

[0147] Possible SNPs found for GPCR7 are listed in Tables 7C and 7D. TABLE 7C SNPs Consensus Base Position Depth Change PAF 419 16 T > C 0.250 699 37 A > T 0.054 821 54 C > T 0.074 929 58 A > G 0.052 961 51 T > — 0.059 972 51 C > — 0.039 1368 7 A > — 0.286

[0148] TABLE 7D SNPs Amino Nucleotide Base Acid Base Position Change Position Change 459 T > C 152 Ser > Pro 566 G > A Silent N/A 967 A > G Silent N/A

[0149] The amino acid sequence of GPCR7 has high homology to other proteins as shown in Table 7E. TABLE 7E BLASTX results for GPCR7 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Reading Score P (N) ptnr:SPTREMBL-ACC:Q9UGF5 OLF 321 aa. 808 2.7e−80 RECP - Homo sapiens,

[0150] The disclosed acid sequence of GPCR7 hs homology to the amino acid sequences shown in the BLAST data listed Table 7F TABLE 7F BLASTP results for GPCR7 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect sp|Q9UGF5 O5U1_HUMAN OLFACTORY 321 154/299 205/299 3e−85 RECEPTOR 5U1 (51%) (68%) (HS6M1-28) emb|CAC43449.1 dM538M10.6 (novel 321 152/299 205/299 1e−80 7 transmembrane (50%) (67%) receptor (rhodopsin family) (olfactory receptor like) protein similar to human HS6M1-28) [Mus musculus] emb|CAC43446.1 dM538M10.3 (novel 304 146/292 198/292 1e−79 7 transmembrane (50%) (67%) receptor (rhodopsin family) (olfactory receptor like) protein) [Mus musculus] emb|CAC43445.1 dM538M10.2 (novel 320 148/299 203/299 2e−78 7 transmembrane (49%) (67%) receptor (rhodopsin family) (olfactory receptor like) protein) [Mus musculus] emb|CAC43448.1 dM538M10.5 (novel 312 142/299 202/299 9e−78 7 transmembrane (47%) (67%) receptor (rhodopsin family) (olfactory receptor like) protein similar to human HS6M1-28) [Mus musculus]

[0151] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 7G.

[0152] Table 7H lists the domain description from DOMAIN analysis results against GPCR7. This indicates that the GPCR7 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 7H Domain Analysis of GPCR7 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO: 76) Length = 254 residues, 100.0% aligned Score = 99.0 bits (245), Expect = 4e−22 GPCR7: 45 GNLLIIILTTLDVHLQTPMYFFLRNLSPLDFCYISVTIPKSIVSSLTHDTSISFFGCALQ 104 ||||+|++      |+||    || ||+  |  ++   | ++   +  |       | | Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR7: 105 AFFFMDLATTEVAILTVMSYDRYMAICRPLHYEVIINQGVCLRMMAMSWLSGVICGFMHV 164    |+      + +|| +| |||+||  || |  |        ++ + |+  ++      + Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRRAKVLILLVWVLALLLSLPPL 120 GPCR7: 165 IATFSLPFCCGRNRIRQFFCNIPQLLSLLDPKVITIEIGVMVFGTSLVIISFVVITLSYMY 224 + ++       |         + +      + |+  |+     ||  + ++ ||     Gnl|Pfam|pfam00001: 121 LFSWLRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRA 180 GPCR7: 225 IFSVIMRIPSKEGRSKTFSTCIPHLVVVTLFMISGSIAYVKPISNSPPVLDV----FLSA 280      ++  |   |       + +| |  ++    +  +  +        +     ++ Fnl|Pfam|pfam00001: 181 RSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITL 240 GPCR7: 281 FYTVVPPTLNPVIY 294 +   |   |||+|| Gnl|Pfam|pfam00001: 241 WLAYVNSCLNPIIY 254

[0153] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR7 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the rhodopsin-like GPCR family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: disorders of the olfactory system reproductive system, dendritic cells, NK cells and mast cell/basophils (based on the expression of olfactory receptors like genes in these organs) and other diseases, disorders and conditions of the like and other diseases, disorders and conditions of the like.

[0154] Based on the Taqman results, the presence of the novel GPCR7 on NK cells implies some role for GPCR7 and its ligand in either the trafficking or the effector action of NK cells to sites of inflammation, transplantation, tumor sites or infection. As NK cells are of importance in the eradication of tumors as well as virally infected cells, GPCR7 may play a role in NK cell action in tumor rejection, where the ligand could be used to augment trafficking or effector action of NK cells. Alternatively a mAb could be used to block GPCR7 which could prove useful in transplantation of organs or bone marrow.

[0155] The presence of the orphan chemokine receptor on dendritic cells suggests that GPCR7 and its ligand could be involved in trafficking and localization of dendritic cells in lymphoid organs at sites of antigen presentation. Also ligand action on the dendritic cell may alter the antigen presenting properties of the dendritic cell and direct T cell activation to either Th1, Th2 or a Tr1 cell response. Therefore blockade of this orphan chemokine receptor with a mAb may alter the immune response in terms of magnitude and also the type of response generated. Alternatively the ligand could be used to modulate immune response. Due to this, mAb to the GPCR or its ligand may be of useful on redirecting the immune response in chronic inflammatory diseases such as Rheumatoid Arthritis, Inflammatory Bowel disease, Multiple Sclerosis, atopic dermatitis, allergic rhinitis and asthma between Th1 and Th2 responses.

[0156] The presence of GPCR7 on a cell line KU-812 which has properties of mast cell and basophils suggests that GPCR7 and its ligand may modulate mast cell and basophil trafficking and localization as well as their effector action. Therefore the ligand or a mAb to GPCR7 may prove useful in blocking mast cell action and therefore be of use in diseases/conditions such as asthma, allergy, inflammation and infections.

[0157] The disclosed GPCR7 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR7 epitope is from about amino acids 5 to 10. In additional embodiments, a GPCR7 epitope is from about amino acids 140 to 145, from about amino acids 170 to 175, from 240 to 250, and from 280 to 310. The GPCR7 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0158] GPCR8

[0159] The disclosed GPCR8 nucleic acid of 958 nucleotides (also referred to AC076959_da2) is shown in Table 8A. The disclosed GPCR8 open reading frame (“ORF”) begins with a ATG at nucleotides 4-7 and ending with a TGA codon at nucleotides 934-936. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 8A GPCR8 nucleotide sequence. (SEQ ID NO: 21) AACATGGAAAGCAATCAGACCTGGATCACAGAAGTCATCCTGTTGGGATTCCAGGTGGACCCAGCTCTGGAGTTGTT CCTCTTTGGGTTTTTCTTGCTATTCTACAGCTTAACCCTGATGGGAAATGGGATTATCCTGGGGCTCATCTACTTGG ACTCTAGACTGCACACACCCATGTATGTCTTCCTGTCACACCTGGCCATTGTGGACATGTCCTATGCCTCGAGTACT GTCCCTAAGATGCTAGCAAATCTTGTGATGCACAAAAAAGTCATCTCCTTTGCTCCTTGCATACTTCAGACTTTTTT GTATTTGGCGTTTGCTATTACAGAGTGTCTGATTTTGGTGATGATGTGCTATGATCGGTATGTGGCAATCTGTCACC CCTTGCAATACACCCTCATTATGAACTGGAGAQTGTCCACTGTCCTGGCCTCAACTTGCTCGATATTTAGCTTTCTC TTGGCTCTGGTCCATATTACTCTTATTCTGAGGCTGCCTTTTTGTGGCCCACAAAAGATCAACCACTTTTTCTGTCA AATCATGTCCGTATTCAAATTCCCCTGTGCTGACACTAGGCTCAACCAGGTGGTCCTATTTGCGCGTTCTGCGTTCA TCTTAGTGGGGCCGCTCTGCCTGGTGCTGGTCTCCTACTTGCACATCCTGGTGGCCATCTTGAGGATCCAGTCTGGG GAGGGCCGCAGAAAGGCCTTCTCTACCTGCTCCTCCCACCTCTGCGTGGTGGGGCTTTTCTTTGGCAGCGCCATTGT CATGTACATGGCCCCCAGGTCAAACCATTCTCAAGAACGGAGGAAGATCCTTTCCCTGTTTTACAGCCTTTTCAACC CGATCCTGAACCCCCTCATCTACAGCCTTAGGAATGCAGAGGTGAAAGGGGCTCTAAAGAGAGTCCTTTGGAAACAG AGATCAATGTGAACAATCATTTGAGATATCCTGA

[0160] The GPCR8 the nucleic acid sequence of this invention has 716 of 944 bases (75%) identical to a gb:GENBANK-ID:AR092423|acc:AR092423.1 mRNA from Unknown (Sequence 1 from patent U.S. Pat. No. 5,998,164) (E=1.7e⁻¹⁰⁸).

[0161] The disclosed GPCR8 polypeptide (SEQ ID NO: 22) encoded protein having 310 amino acid residues is presented in Table 8B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR8 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the microbody (peroxisome) with a certainty of 0.3000. The most likely cleavage site for a GPCR8 peptide is between amino acids 46 and 47, at: ILG-LI. TABLE 8B Encoded GPCR8 protein sequence. (SEQ ID NO: 22) MESNQTWITEVILLGFQVDPALELFLFGFFLLFYSLTLMGNGIILGLIYLDSRLHTPMYVFLSHLAIVDMSYASSTV PKMLANLVMHKKVISFAPCILQTFLYLAFAITECLILVMMCYDRYVAICHPLQYTLIMNWRVCTVLASTCWIFSFLL ALVHITLILRLPFCCPQKINHFFCQIMSVFKLACALTRLNQVVLFAGSAFILVGPLCLVLVSYLHILVAILRIQSGE GRRKAFSTCSSHLCVVGLFFGSAIVMYMAPRSNHSQERRKILSLFYSLFMPILNPLIYSLRNAEVKCALKRVLWKQR SM

[0162] The disclosed GPCR8 amino acid sequence of the protein of the invention was found to have 188 of 310 amino acid residues (60%) identical to, and 238 of 310 amino acid residues (76%) similar to, the 310 amino acid residue ptnr:SPTREMBL-ACC:O95047 protein from Homo sapiens (Human) (WUGSC:H_DJ0988G15.2 PROTEIN) (E=1.1e⁻⁹⁸).

[0163] GPCR8 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0164] Possible SNPs found for GPCR8 are listed in Tables 8C and 8D TABLE 8C SNPs Consensus Base Position Depth Change PAF 147 11 C > T 0.182

[0165] TABLE 8D SNPs Amino Nucleotide Base Acid Base Position Change Position Change 143 T > C 47 Leu > Pro 257 T > C 85 Val > Ala 374 C > T 124 Ala > Val 770 T > C 256 Val > Ala 788 G > A 262 Arg > Lys 794 A > G 264 Asn > Ser

[0166] The amino acid sequence of GPCR8 has high homology to other proteins as shown in Table 8E. TABLE 8E BLASTX results for GPCR8 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) Ptnr:SPTREMBL-ACC:095407 Protein - 310 aa. 981 1.1e−98 Homo sapiens,

[0167] The disclosed GPCR8 has homology to the amino acid sequences shown in the BLASTP data listed in Table 8F. TABLE 8F BLASTP results for GPCR8 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|14747795|ref XP_04 hypothetical 310 190/310 240/310 2e−86 2034.1 protein XP_042034 (61%) (77%) [Homo sapiens] gi|13929212|ref NP_11 olfactory 310 188/310 238/310 1e−85 2170.1 receptor, family (60%) (76%) 2 , subfamily A, member 4 [Homo sapiens] gi|2921716|gb|AAC3963 olfactory 217 168/217 189/217 2e−80 3.1 receptor (77%) (86%) [Homo sapiens] gi|2921710 gb AAC3963 olfactory 217 167/217 188/217 7e−80 0.1 receptor (76%) (85%) [Homo sapiens] gi|15293775|gb|AAK950 olfactory 217 167/217 188/217 1e−79 80.1 receptor (76%) (85%) [Homo sapiens]

[0168] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 8G.

[0169] Table 8H lists the domain description from DOMAIN analysis results against GPCR8. This indicates that the GPCR8 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 8H Domain Analysis of GPCR8 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO: 82) Length = 254 residues, 100.0% aligned Score = 115 bits (288), Expect = 4e−27 GPCR8: 40 GNGIILGLTYLDSRLETPMYVFLSHLAIVDMSYASSTVPKMLANLVMHKKVISPAPCILQ 99 || +++ +|    +| ||   +|| +||+ |+ +  +  |  |  ||    |    | | | Gnl|Pfam|pfam00001: 1 GNLLVTLVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR8: 100 TFLYLAFAITECLILVMMCYDRYVAICHPLQYTLIMNWRVCTVLASTCWIFSFLLALVHI 159   |++       |+|  +  |||+|| |||+|  |   |    ||    |+ + ||+|  + Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR8: 160 TLILRLPFCGPQKINHFFCQIMSVFKLACADTRLNQVVLFAGSAFILVGPLCLVLVSYLH 219             ++ |   | |            + +  +   +    | || ++|| | Gnl|Pfam|pfam00001: 121 LFSWLRT---VEEGNTTVCLIDFPE------ESVKRSYVLLSTLVGFVLPLLVILVCYTR 171 GPCR8: 220 ILVA--------ILRIQSGEGRRKAFSTCSSHLCVVGLFFGSAIVMYMAP----RSNHS 266 ||            |+ +|    |+ |       +  |  +    ||+ + Gnl|Pfam|pfam00001: 172 ILRTLRKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLDSLCLLSIWRV 231 GPCR8: 267 QERRKILSLFYSLFNPILNPLIY 289      +++|+ +  |  |||+|| Gnl|Pfam|pfam00001: 232 LPTALLITLWLAYVNSCLNPIIY 254

[0170] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR8 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: familial Mediterranian fever, developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0171] The disclosed GPCR8 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR8 epitope is from about amino acids 230 to 240. In additional embodiments, a GPCR8 epitope is from about amino acids 260 to 270, from about amino acids 290 to 300. The GPCR8 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0172] GPCR9

[0173] The disclosed GPCR9 nucleic acid of 968 nucleotides (also referred to as AC073364_da1) is shown in Table 9A. The disclosed GPCR9 open reading frame (“ORF”) begins with a ATG at nucleotides 16-18 and ending with a TAA codon at nucleotides 961-963. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 9A GPCR9 nucleotide sequence. (SEQ ID NO:23) AGCTCTACTAGAAAT ATGGAGAGCAGAAACCAATCAACAGTGACTGAATTTATCTTCACTGGATTCCCTCAGCTTCA GGATGGTAGTCTCCTGTACTTCTTTCCTTTACTTTTCATCTATACTTTTATTATCATTGATAACTTATTAATCTTCT CTGCTGTAAGGCTGGACACCCATCTCCACAACCCCATGTATAATTTTATCAGTATATTTTCCTTTCTGGAGATCTGG TACACCACAGCCACCATTCCCAAGATGCTCTCCAACCTCATCAGTGAAAGAAGGCCATCTCAATGACTGGCTGCAT CTTGCAGATGTATTTCTTCCACTCACTTGAAAACTCAGAGGGGATCTTGCTGACCACCATGGCCATTGACAGATACG TTGCCATCTGCAACCCTCTTCGCTATCAAATGATCATGACCCCCCGGCTCTGTGCTCAACTCTCTGCAGGTTCCTGC CTCTTCGGTTTCCTTATCCTGCTTCCCGAGATTGTGATGATTTCCACACTGCCTTTCTGTGGGCCCAACCAAATCCA TCAGATCTTCTGTGACTTGGTCCCTGTGCTAAGCCTGGCCTGTACAGACACGTCCATGATTCTGATTGAGGATGTGA TTCATGCTGTGACCATCATCATTACCTTCCTAATCATTGCCCTGTCCTATGTAAGAATTGTCACTGTGATATTGAGG ATTCCCTCTTCTGAAGGGAGGCAAAGGCTTTTTCTACCTGTGCAGGCCACCCCATGGTCTTCCCGATATTCTTTGG CAGTGTATCACTCATGTACTTGCGTTTCAGCGACACTTATCCACCAGTTTTGGACACACCCATTGCACTGATGTTTA CTGTACTTGCTCCATTCTTCAATCCCATCATTTATAGCCTGAGAAACAAGGACATGAACAATGCGATTAAAAAACTG TTCTGTCTTCAAAAAGTGTTGAACAAGCCTGGAGGTTAA TACAG

[0174] The GPCR9 the nucleic acid sequence of this invention has 670 of 954 bases (70%) identical to a gb:GENBANK-ID:AP002533|acc:AP002533.1 mRNA from Homo sapiens (Homo sapiens genomic DNA, chromosome 1q22-q23, CD1 region, section 2/4 (E=1.5e⁻⁸⁷).

[0175] The disclosed GPCR9 polypeptide (SEQ ID NO: 24) encoded protein having 315 amino acid residues is presented in Table 3B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR9 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the mitochondrial inner membrane with a certainty of 0.3000. The most likely cleavage site for a GPCR9 peptide is between amino acids 50 and 51, at: AVR-LD. TABLE 9B Encoded GPCR9 protein sequence. (SEQ ID NO:24) MESRNQSTVTEFIFTGFPQLQDGSLLYFFPLLFIYTFIIIDNLLIFSAVRLDTHLHNPMYNFISIFSFLEIWYTTAT IPKMLSNLISEKKAISMTGCILQMYFFHSLENSEGILLTTMAIDRYVAICNPLRYQMIMTPRLCAQLSAGSCLFGFL ILLPEIVMISTLPFCGPNQIHQIFCDLVPVLSLACTDTSMILIEDVIHAVTIIITFLIIALSYVRIVTVILRIPSSE GRQKAFSTCAGHPMVFPIFFGSVSLMYLRFSDTYPPVLDTAIALMFTVLAPFFNPIIYSLRNKDMNNAIKKLFCLQK VLNKPGG

[0176] The disclosed GPCR9 amino acid sequence of the protein of the invention was found to have 135 of 304 amino acid residues (44%) identical to, and 192 of 304 amino acid residues (63%) similar to, the 321 amino acid residue ptnr:SPTREMBL-ACC:Q9UGF6 protein from Homo sapiens (Human) (BA150A6.2 (NOVEL 7 TRANSMEMBRANE RECEPTOR (RHODOPSIN FAMILY) (OLFACTORY RECEPTOR LIKE) PROTEIN (HS6M1-21) (E=1.7e⁻⁶⁵).

[0177] GPCR9 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue. Those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0178] Possible SNPs found for GPCR9 are listed in Tables 9C. The SNP located at 758 bp is also referred to as variant 13374101. TABLE 9C SNPs Amino Nucleotide Base Acid Base Position Change Position Change 25 A > G 4 Arg > Gly 186 C > T Silent N/A 468 C > T Silent N/A 697 C > T 228 Pro > Ser 713 G > A 233 Arg > Lys 758 C > T 248 Pro > Leu

[0179] The amino acid sequence of GPCR9 has high homology to other proteins as shown in Table 9D. TABLE 9D BLASTX results for GPCR9 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) ptnr:SPTREMBL-ACC:Q9UGF6 OLF 321 aa. 668 1.7e−65 RECP - Homo sapiens,

[0180] The disclosured GPCR9 has homology to the amino acid sequences shown in the BLASTP data listed in Table 9E. TABLE 9E BLASTP results for GPCR9 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|13562084|ref|NP_11 olfactory 321 135/304 192/304 9e−59 0503.1 receptor, family (44%) (62%) 5, subfamily V member 1 [Homo sapiens] gi|7242165|ref|NP_035 olfactory 327 131/308 190/308 8e−58 113.1| receptor 41 (42%) (61%) [Mus musculus] gi|13928994|ref NP_11 olfactory 327 134/308 191/308 2e−57 3898.1| receptor 41 (43%) (61%) [Rattus norvegicus] gi|12007416|gb|AAG451 m51 olfactory 314 139/303 189/303 2e−57 89.1 receptor (45%) (61%) [Mus musculus] gi|14596246|emb|CAC43 dM538M10.1 (novel 317 134/306 186/306 3e−57 444.1| 7 transmembrane (43%) (59%) receptor (rhodopsin family) (olfactory receptor like) protein similar to human HS6M1-21) [Mus musculus]

[0181] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 9F.

[0182] Table 9G lists the domain description from DOMAIN analysis results against GPCR9. This indicates that the GPCR9 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 9G Domain Analysis of GPCR9 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:88) Length = 254 residues, 99.6% aligned Score = 95.5 bits (236), Expect = 4e−21 GPCR9: 42 NLLIFSAVRLDTHLHNPMYNFISTFSFLEIWYTTATIPKMLSNLISEKKAISMTGCILQM 101 |||+   +     |  |   |+   +  ++ +     |  |  |+          | | Gnl|Pfam|pfam00001: 2 NLLVILVILRTKKLRTPTNFLLNAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLVG 61 GPCR9: 102 YFFHSLENSEGILLTTMAIDRYVAICNPLRYQMIMTPRLCAQLSAGSCLFGFLILLPEIV 161   |     +  +||| ++||||+|| +||||+ | |||    |     +   |+ || ++ Gnl|Pfam|pfam00001: 62 ALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPLL 121 GPCR9 162 MISTLPFCGPNQIHQIFCDLVPVLSLACTDTSMILIEDVIHAVTIIITFLI-IALSYVRI 220           |    +       +  +    | ++   +   | ++    |   | Gnl|Pfam|pfam00001: 122 FSWLRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRAR 181 GPCR9: 221 VTVILRIPSSEGRQKAFSTCAGHPMVF----PIFFGSVSLMYLRFSDTYPPVLDTAIALM 276     |+  ||  |+ |        +      |     +       |         | | Gnl|Pfam|pfam00001: 182 SQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITLW 241 GPCR9: 277 FTVLAPFFNPIIY 289    +    ||||| Gnl|Pfam|pfam00001: 242 LAYVNSCLNPIIY 264

[0183] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR9 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: familial Mediterranian fever, developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy (DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0184] The disclosed GPCR9 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR9 epitope is from about amino acids 50 to 10. In additional embodiments, a GPCR9 epitope is from about amino acids 60 to 65, from about amino acids 140 to 145, from 240 to 242, and from 290 to 310. The GPCR9 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0185] GPCR10

[0186] The disclosed GPCR10 nucleic acid of 928 nucleotides (also referred to as CG55732-01) is shown in Table 10A. The disclosed GPCR10 open reading frame (“ORF”) begins with a TTT codon which codes for the amino acid phenylalanine at nucleotides 24 and ending with a TAA codon at nucleotides 845-847. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 10A GPCR10 nucleotide sequence. (SEQ ID NO:25) G TTTTCTGTCATCTACATCAACGCCATGATAGGAAATGTGCTCATTGTGGTCACCATCACTGCCAGCCCATCACTGA GATCCCCCATGTACTTTTTCCTGGCCTATCTCTCCTTTATTGATGCCTGCTATTCCTCTGTCAATGCCCCTAAGCTG ATCACAGATTCACTCTATGAAAACAAGACTATCTTATTCAATGGATGTATGACTCAAGTCTTTGGAGAACATTTTTT CAGAGGTGTTGAGGTCATCCTACTTACTGTAATGGCCTATGACCACTATGTGGCCATCTGCAAGCCCTTGCACTATA CCACCATCATGAAGAAGCATGTTTGTAGCCTGCTAGTGGGAGTGTCATGGGTAGGAGGCTTTCTTCATGCAACCATA CAGATCCTCTTCATCTGTCAATTACCTTTCTGTGGTCCTAATGTCATAGATCACTTTATGTGTGATCTCTACACTTT GATCAATCTTGCCTGCACTAATACCCACACTCTAGGACTCTTCATTGCTGCCAACAGTGGGTTCATATGCCTGTTAA ACTGTCTCTTGCTCCTGGTCTCCTGCGTGCTCATACTGTACTCCTTAAAGACCCACAGCTTAGAGGCAAGCCACGAA GCCCTCTCTACCTGTGTCTCCCACATCACAGTTGTCATCTTATCCTTTATACCCTGCATATTTGTGTACATGACACC TCCAGCTACTTTACCCATTGATAAAGCAGTTGCTGTATTCTACACTATGATAACTTCTATGTTAAACCCCTTAATCT ACACCTTGAGGAATGCTCAAATGAAAAATGCCATTAGGAAATTGTGTAGTAGGAAAGCTATTTCAAGTGTCAAATAA ATGTGACTGGAGCCCAACATGATTCAACTGAGGCAAGGGTCAAAAGGACATTTTGGGTAATGCCAGCAAAGGAATAC TTAT

[0187] The GPCR10 the nucleic acid sequence of this invention has 575 of 821 bases (70%) identical to a gb:GENBANK-ID:AB030896|acc:AB030896.1 mRNA from Mus musculus (Mus musculus gene for odorant receptor A16, complete cds) (E=3.0e⁻⁷⁶).

[0188] The disclosed GPCR10 polypeptide (SEQ ID NO: 26) encoded protein having 281 amino acid residues is presented in Table 10B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR10 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6400. In other embodiments, it is localized at the Golgi body with a certainty of 0.4600, at the endoplasmic reticulum (membrane) with a certainty of 0.3700 or at the endoplasmic reticulum (lumen) with a certainty of 0.1000. The most likely cleavage site for a GPCR1 0 peptide is between amino acids 44 and 45, at: CYS-SV. TABLE 10B Encoded GPCR10 protein sequence. (SEQ ID NO:26) FSVIYINAMIGNVLIVVTITASPSLRSPMYFFLAYLSFIDACYSSVNAPKLITDSLYENKTILFNGCMTQVFGEHFF RGVEVILLTVMAYDHYVAICKPLHYTTIMKKHVCSLLVGVSWVGGFLHATIQILFICQLPFCGPNVIDHPMCDLYTL INLACTNTHTLGLFIAANSGFICLLNCLLLLVSCVVILYSLKTHSLEAREEALSTCVSHITVVILSFIPCIFVYMRP PATLPIDKAVAVFYTMITSMLNPLIYTLRNAQMKNAIRKLCSRKAISSVK

[0189] The disclosed GPCR10 amino acid sequence of the protein of the invention was found to have 182 of 277 amino acid residues (65%) identical to, and 221 of 277 amino acid residues (79%) similar to, the 308 amino acid residue ptnr:SPTREMBL-ACC:Q9R0K2 protein from Mus musculus (Mouse) (ODORANT RECEPTOR MOR18) (E=7.9e⁻⁹⁹).

[0190] GPCR10 disclosed in this invention is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.

[0191] Possible SNPs found for GPCR10b are listed in Table 10C. TABLE 10C SNPs Consensus Base Position Depth Change PAF 611 7 T > G 0.429

[0192] The amino acid sequence of GPCR10 has high homology to other proteins as shown in Table 10D. TABLE 10D BLASTX results for GPCR10 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) ptnr:SPTREMBL-ACC:Q9R0K2 308 aa. 983 7.9e−99 ODOR RECP - Mus Musculus,

[0193] The disclosed GPCR 10 has homology to the amino acid sequences shown in the BLASTP data listed in Table 10E. TABLE 10E BLASTP results for GPCR10 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|15293735|gb|AAK950 olfactory 213 211/213 212/213 1e−95 60.1 receptor (99%) (99%) [Homo sapiens] gi|11496249|ref NP_06 odorant receptor 308 182/277 221/277 3e−89 7343.1 16 [Mus musculus] (65%) (79%) gi|11464995|ref NP_06 gene for odorant 302 169/271 214/271 1e−84 5261.1 receptor A16 (62%) (78%) [Mus musculus] gi|423702|pir |S29710 olfactory 307 162/271 204/271 1e−73 receptor OR18 - (59%) (74%) rat gi|3983372 gb AAD1331 olfactory 220 157/220 177/220 6e−73 4.1 receptor C3 (71%) (80%) [Mus musculus]

[0194] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 10F.

[0195] Table 10G lists the domain description from DOMAIN analysis results against GPCR10. This indicates that the GPCR10 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 10G Domain Analysis of GPCR10 gnl|Pfam|pfam00001:, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:94) Length = 254 residues, 100.0% aligned Score = 157/220 (71%), Expect= 1e−18 GPCR10: 11 GNVLIVVTITASPSLRSPMYFFLAYLSFIDACYSSVNAPKLITDSLYENKTILFNGCMTQ 70 ||+|+++ |  +  ||+|   ||  |+  |  +     |  +   +  +       | Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLV 60 GPCR10: 71 VFGEHFFRGVEVILLTVMAYDHYVAICKPLHYTTIMKKHVCSLLVGVSWVGGFLHATIQI 130            ++||| ++ | |+||  || |  |       +|+ + ||   | +   + Gnl|Pfam|pfarm00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR10: 131 LFICQLPFCGPNVTDEFMCDLYTLTNACTNTHTLGLFIAANSGFICLLNCLLLLVSCVV 190 ||         |     +      +  +     ||  |+      +     +|  + Gnl|Pfam|pfam00001: 121 LFSWLRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRA 180 GPCR10: 191 ILYSLKTHSLEARHEALSTCVSHITVVILSFIPC-IFVYMRP------PATLPIDKAVAV 243            +  +|    +  + | +| ++|  | + +           ||    + + Gnl|Pfam|pfam00001: 181 RSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITL 240 GPCR10: 244 FYTMITSMLNPLIY 257 +   + | |||+|| Gnl|Pfam|pfam00001: 241 WLAYVNSCLNPIIY 254

[0196] The protein similarity information, expression pattern, and map location for the olfactory receptor-like GPCR10 protein and nucleic acid disclosed herein suggest that this olfactory receptor may have important structural and/or physiological functions characteristic of the olfactory receptor family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders of the like.

[0197] The disclosed GPCR10 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR10 epitope is from about amino acids 50 to 55. In additional embodiments, a GPCR10 epitope is from about amino acids 57 to 60, from about amino acids 60 to 62, from 67 to 70, from 95 to 105, from 195 to 205 and from 260 to 275. The GPCR10 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0198] GPCR11

[0199] The disclosed GPCR11 nucleic acid of 971 nucleotides (also referred to as sggc_draft_ba656o22_20000731_da1) is shown in Table 11A. The disclosed GPCR11 open reading frame (“ORF”) begins with a ATG at nucleotides 3-5 and ending with a TAG codon at nucleotides 963-965. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 11A GPCR11 nucleotide sequence. (SEQ ID NO:27) CA ATGATGGAAATAGCCAATGTGAGTTCTCCAGAAGTCTTTGTCCTCCTGGGCTTCTCCGCACGACCCTCACTAGAA ACTGTCCTCTTCATAGTTGTCTTGAGTTTTTACATGGTATCGATCTTGGGCAATGGCATCATCATTCTGGTCTCCCA TACAGATGTGCACCTCCACACACCTATGTACTTCTTTCTTGCCACCTCTCCTTCCTGGACATGAGCTTCACCACGA GCATTGTCCCACAGCTCCTGGCTAACCTCTGGGGACCACAGAAAACCATAAGCTATGGAGGGTGTGTGGTCCAGTTC TATATCTCCCATTGGCTGGGGGCAACCGAGTGTGTCCTGCTGGCCACCATGTCCTATGACCGCTACGCTGCCATCTG CAGGCCACTCCATTACACTGTCATTATGCATCCACAGCTTTGCCTTCGGCTAGCTTTGGCCTCCTGGCTGGGGGGTC TGACCACCAGCATGGTGGGCTCCACGCTCACCATGCTCCTACCGCTGTGTGGGAACAATTGCATCGACCACTTCTTT TGCGAGATGCCCCTCATTATGCAACTGGCTTGTGTGGATACCAGCCTCAATGAGATGGAGATGTACCTGGCCAGCTT TGTCTTTGTTGTCCTGCCTCTGGGGCTCATCCTGGTCTCTTACGGCCACATTGCCCGGGCCGTGTTGAAGATCAGGT CAGCAGAAGGGCGGAGAAAGGCATTCAACACCTGTTCTTCCCACGTGGCTGTGGTGTCTCTGTTTTACGGGAGCATC ATCTTCATGTATCTCCAGCCAGCCAAGAGCACCTCCCATGAGCAGGGCAAGTTCATAGCTCTGTTCTACACCGTAGT CACTCCTGCGCTGAACCCAGTTATTTACAACCTGAGGAACACGGAGGTGAAGAGCGCCCTCCGGCACATGGTATTAG AGAACTGCTGTGGCTCTGCAGGCAAGCTGGCGCAAATTTAG AGACTC

[0200] The GPCR11 the nucleic acid sequence has 601 of 906 bases (66%) identical to a Homo sapiens olfactory receptor-like protein (OR2C1) gene mRNA (GENBANK-ID: AF098664|acc:AF098664) (E=1.9e⁻⁶⁷).

[0201] The disclosed GPCR11 polypeptide (SEQ ID NO: 28) encoded protein having 320 amino acid residues is presented in Table 3B using the one-letter amino acid code. TABLE 11B Encoded GPCR11 protein sequence. (SEQ ID NO:28) MMEIANVSSPEVFVLLGFSARPSLETVLFIVVLSFYMVSILGNGIIILVSHTDVHLHTPMYFFLANLSFLDMSFTTS IVPQLLANLWGPQKTISYGGCVVQFYISHWLGATECVLLATMSYDRYAAICRPLHYTVIMHPQLCLGLALASWLGGL TTSMVGSTLTMLLPLCGNNCIDHFFCEMPLIMQLACVDTSLNEMEMYLASFVFVVLPLGLILVSYGHIARAVLKIRS AEGRRKAFNTCSSHVAVVSLFYGSIIFMYLQPAKSTSHEQGKFIALFYTVVTPALNPVIYNLRNTEVKSALRHMVLE NCCGSAGKLAQI

[0202] The disclosed GPCR11 amino acid sequence of the protein of the invention was found to have 181 of 305 amino acid residues (59%) identical to, and 232 of 305 residues (76%) positive with, the 312 amino acid residue OLFACTORY RECEPTOR 15 (OR3) protein from Mus musculus (ptnr: SWISSPROT-ACC:P23275) (E=1.8e⁻⁹⁷).

[0203] Possible SNPs found for GPCR11 are listed in Tables 11C. TABLE 11C SNPs Amino Nucleotide Base Acid Base Position Change Position Change 71 A > G Silent N/A 185 C > T Silent N/A 389 G > C 129 Arg > Ser 541 G > A 180 Cys > Tyr 780 T > C 260 Tyr > His

[0204] The amino acid sequence of GPCR11 has high homology to other proteins as shown in Table 11D. TABLE 11D BLASTX results for GPCR11 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) ptnr:SWISSPROT-ACC:P23725 OLF 312 aa. 977 1.8e−97 RECP - Mus Musculus,

[0205] The disclosed GPCR11 has homology to the amino acid sequences shown in the BLASTP data listed in Table 11E. TABLE 11E BLASTP results for GPCR11 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|6679170 ref|NP_032 olfactory 312 181/305 232/305 3e−96 788.1| receptor 15 (59%) (75%) [Mus musculus] gi|13624329|ref|NP_11 olfactory 320 172/305 229/305 2e−92 2165.1 receptor, family (56%) (74%) 2, subfamily W, member 1 [Homo sapiens] gi|12054431|emb CAC20 olfactory 320 172/305 229/305 3e−92 523.1| receptor (56%) (74%) [Homo sapiens] gi|12054355|emb CAC20 olfactory 312 175/306 230/306 4e−92 485.1| receptor (57%) (74%) [Homo sapiens] gi|12054429|emb CAC20 olfactory 320 172/305 228/305 5e−92 522.1| receptor [Homo sapiens] (56%) (74%)

[0206] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 11F.

[0207] Table 11G lists the domain description from DOMAIN analysis results against GPCR11. This indicates that the GPCR11 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 11G Domain Analysis of GPCR11 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:100) Length = 254 residues, 100.0% aligned Score = 102 bits (254), Expect = 3e−23 GPCR11: 42 GNGIIILVSHTDVHLHTPMYFFLANLSFLDMSFTTSIVPQLLANLWGPQKTISYGGCVVQ 101 || ++|||      | ||   || ||+  |+ |  ++ |  |  | |         | + Gnl|Pfam|pfam00001: 1 GNLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFCDALCKLV 60 GPCR11: 102 FYISHWLGATECVLIATMSYDRYAAICRPLHYTVIMHPQLCLGLALASWLGGLTTSMVGS 161   +    |    +||  +| ||| ||  || |  |+    | |  |+  |  |+ Gnl|Pfam|pfam00001: 61 GALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPL 120 GPCR11: 162 TLTMLLPLCGNNCIDHFFCEMPLIMQLACVDTSLNEMEMYLASFVFVVLPLGLILVSYGH 221   + |         +   | +    +       |      |++ |  |||| +||| | Gnl|Pfam|pfam00001: 121 LFSWLRT---VEEGNTTVCLIDFPEESVKRSYVL------LSTLVGFVLPLLVILVCYTR 171 GPCR11: 222 IARAV---------LKIRSAEGRRKAFNTCSSHVAVVSLFYGSIIFMYLQPAKSTSHEQ- 271 | | +         || ||+  |+ |       |  |  +    | + |      |  + Gnl|Pfam|pfam00001: 172 ILRTLRKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRV 231 GPCR11: 272 ---GKFIALFYTVVTPALNPVIY 291       | |+   |   |||+|| Gnl|Pfam|pfam00001: 232 LPTALLITLWLAYVNSCLNPIIY 254

[0208] GPCR12

[0209] The disclosed GPCR12 nucleic acid of 958 nucleotides (also referred to as ba407h12_da1) is shown in Table 12A. The disclosed GPCR12 open reading frame (“ORF”) begins with a ATG at nucleotides 3-5 and ending with a TAA codon at nucleotides 1162-1164. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 12A GPCR12 nucleotide sequence. (SEQ ID NO:29) CT ATGGAGCAGAGCAATTATTCCGTGTATGCCGACTTTATCCTTCTGGGTTTGTTCAGCAACGCCCGTTTCCCCTGG CTTCTCTTTGCCCTCATTCTCCTGGTCTTTGTGACCTCCATAGCCAGCAACGTGGTCAAGATCATTCTCATCCACAT AGACTCCCGCCTCCACACCCCCATGTACTTCCTGCTCAGCCAGCTCTCCCTCAGGGACATCTTGTATATTTCCACCA TTGTGCCCAAAATGCTGGTCGACCAGGTGATGAGCCAGAGAGCCATTTCCTTTGCAGGATGCACTGCCCAACACTTC CTCTACTTGACCTTAGCAGGGGCTGAGTTCTTCCTCCTAGGACTCATGTCCTGTGATCGCTACGTAGCCATCTGCAA CCCTCTGCACTATCCTGACCTCATGAGCCGCAAGATCTGCTGGTTGATTGTGGCOGCAGCCTGGCTGGGAGGGTCTA TCGATGGTTTCTTGCTCACCCCCGTCACCATGCAGTTCCCCTTCTGTGCCTCTCGGGAGATCAACCACTTCTTCTCC GAGGTGCCTGCCCTTCTGAAGCTCTCCTGCACGGACACATCAGCCTACGAGACAGCCATGTATGTCTGCTGTATTAT GATGCTCCTCATCCCTTTCTCTGTGATCTCGGGCTCTTACACAAGAATTCTCATTACTGTTTATAGGATGAGCGAGG CAGAGGGGAGGCGAAAGGCTGTGGCCACCTGCTCCTCACACATGGTCCTTGTCAGCCTCTTCTATGCGGCTGCCATG TACACATACGTGCTGCCTCATTCTTACCACACCCCTGAGCAGGACAAAGCTGTATCTGCCTTCTACACCATCCTCAC TCCCATGCTCAATCCACTCATTTACAGCCTTAGGAACAAGGATGTCACGGGGGCCCTACAGAAGGTTGTTGGGAGGT GTGTGTCCTCAGGAAAGGTAACCACTTTCTAA AC

[0210] The disclosured GPCR12 polypeptide (SEQ ID NO: 30) encoded protein having 317 amino acid residues is presented in Table 3B using the one-letter amino acid code. TABLE 12B Encoded GPCR12 protein sequence. (SEQ ID NO:30) MEQSNYSVYADFILLGLFSNARFPWLLFALILLVFVTSIASNVVKIILIHIDSRLHTPMYFLLSQLSLRDILYISTI VPMLVDQVMSQRAISFAGCTAQHFLYLTLAGAEFFLLGLMSCDRYVAICNPLHYPDLMSRKICWLTVAAAWLGGSI DGFLLTPVTMQFPFCASREINHFFCEVPALLKLSCTDTSAYETANYVCCIMMLLIPFSVISGSYTRILITVYRMSEA EGRRKAVATCSSHMVVVSLFYGAAMYTYVLPHSYHTPEQDKAVSAFYTILTPMLNPLIYSLRNKDVTGALQKVVGRC VSSGKVTTF

[0211] The disclosured GPCR12 amino acid sequence has 146 of 313 amino acid residues (46%) identical to, and 215 of 313 residues (68%) positive with, the Rattus norvegicus (rat) 313 amono acid residue olfactory receptor protein (ptnr: SPTREMBL-ACC:Q63394)(E=1.0e⁻⁷⁴).

[0212] possible SNPs found for GPCR12 are listed in Tables 12C. TABLE 12C SNPs Amino Nucleotide Base Acid Base Position Change Position Change 62 C > T Silent N/A 136 A > T 45 Lys > Met 216 T > C Silent N/A 287 A > T Silent N/A 361 G > A 120 Cys > Tyr 403 A > T 134 Asp > Val 896 G > A Silent N/A

[0213] The amino acid sequence of GPCR12 has high homology to other proteins as shown in Table 12D. TABLE 12D BLASTX results for GPCR12 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) Ptnr:SPTREMBL-ACC:Q63394 OL1 313 aa . . . 755 1.0e−74 RECP - Rattus norv,

[0214] The disclosed GPCR12 has homology to the amino acid sequences shown in the BLASTP data listed in Table 12E. TABLE 12E BLASTP results for GPCR12 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|14423768|sp|O43869 OLFACTORY 311 217/307 252/307  e−110 |O2T1_HUMAN RECEPTOR 2T1 (70%) (81%) (OLFACTORY RECEPTOR 1-25) (OR1-25) gi|3983382 gb AAD1331 olfactory 223 168/223 191/223 2e−87 9.1 receptor E3 (75%) (85%) [Mus musculus] gi|2921628 gb AAC3961 olfactory 216 163/216 185/216 2e−84 1.1 receptor (75%) (85%) [Homo sapiens] gi|12007423|gb|AAG451 T2 olfactory 316 157/309 212/309 1e−76 96.1 receptor (50%) (67%) [Mus musculus] gi|12007424|gb|AAG451 T3 olfactory 315 156/310 212/310 4e−75 97.1 receptor (50%) (68%) [Mus musculus]

[0215] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 12F.

[0216] Table 12G lists the domain description from DOMAIN analysis results against GPCR12. This indicates that the GPCR12 sequence has properties similar to those of other proteins known to contain this domain as well as to the 254 amino acid 7tm domain itself. TABLE 12G Domain Analysis of GPCR12 gn1|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:106) Length = 254 residues, 99.6%aligned Score = 105 bits (262), Expect = 4e−24 GPCR12: 42 NVVKIILIHTDSRLHTPMYFLLSQLSLRDILYISTIVPKMLVDQVMSQRAISFAGCTAQH 101 |++ |++|    +| ||    |  |++ |+|++ |+ |  |   |        | | Gn1|Pfam|pfam00001: 2 NLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLVG 61 GPCR12: 102 FLYLTLAGAEFFLLGLMSCDRYVAICNPLHYPDLMSRKICWLIVAAAWLGGSIDGFLLTP 101  |++    |   ||  +| |||+|| +|| |  + + +   +++   |+   |+   +   |  | Gn1|Pfam|pfam00001: 62 ALFVVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALL---LSLP 118 GPCR12: 162 VTMQFPFCASREINHFFCEVPALLKLSCTDTSAYETAMYVC-CIMMLLIPFSVISGSYTR 220   +        | |   |       |      + + +  +   ++  ++|  ||   ||| Gn1|Pfam|pfam00001: 119 PLLFSWLRTVEEGNTTVC-------LIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTR 171 GPCR12: 221 ILITV---------YRMSEAEGRRKAVATCSSHMVVVSLFYG----AAMYTYVLPHSYHT 267 || |+          +   +  |+ |       +| |  +        + +  |   + Gn1|Pfam|pfam00001: 172 ILRTLTKRARSQRSLKRRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRV 231 GPCR12: 268 PEQDKAVSAFYTILTPMLNPLIY 290       ++ +   +   |||+|| Gn1|Pfam|pfam00001: 232 LPTALLITLWLAYVNSCLNPIIY 254

[0217] GPCR13

[0218] The disclosed GPCR13 nucleic acid of 1013 nucleotides (also referred to as AC074365_da1) is shown in Table 13A. The disclosed GPCR13 open reading frame (“ORF”) begins with a ATG at nucleotides 9-11 and ending with a TGA codon at nucleotides 1011-1013. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 13A GPCR13 nucleotide sequence. (SEQ ID NO:31) CCTATGTG ATGTGTTATCTTTCTCAGCTATGCCTCAGCCTTGGGGAACACACTTTACATATGGGGATGGTGAGACAT ACCAATGAGAGCACCTAGCAGGTTTCATCCTTTTAGGGTTTTCTGATTATCCTCAGTTACAGAAGGTTCTATTTGT GCTCATATTGATTCTGTATTTACTAACTATTTTGGGGATACCACCATCATTCTGGTTTCTCGTCTGGAACCCAAGC CTCATATGCCGATGTATTTCTTCCTTTCTCATCTCTCCTTCCTGTACCGCTGCTTCACCAGCAGTGTTATTCCCCG CTCCTGGTAAACCTGTGGGAACCCATGAAAACTATCGCCTATGGTGGCTGTTTGGTTCACCTTTACAACTCCCATGC CCTGGGATCCACTGAGTGCGTCCTCCCGGCTCTGATGTCCTGTGACCGCTATGTGGCTGTCTGCCGTCCTCTCCATT ACACTGTCTTAATGCATATCCATCTCTGCATGGCCTTGGCATCTATGGCATGGCTCAGTGGAATAGCCACCACCCTG GTACAGTCCACCCTCACCCTGCAGCTGCCCTTCTGTGGGCATCGCCAAGTGGATCATTTCATCTGCGAGGTCCCTGT GCTCATCAAGCTGGCTTGTGTGGGCACCACGTTTAACGAGGCTGAGCTTTTTGTGGCTAGTATCCTTTTCCTTATAG TGCCTGTCTCATTCATCCTGGTCTCCTCTGGCTACATTGCCCACGAGTGTTGAGGATTAAGTCAGCTACCGGGAGA CAGAAAGCATTCGGGACCTGCTTCTCCCACCTGACAGTGGTCACCATCTTTTATGGAACCATCATCTTCATGTATCT GCAGCCAGCCAAGACTAGATCCAGGGACCAGGGCAAGTTTGTTTCTCTCTTCTACACTGTGGTAACCCGCATGCTTA ACCCTCTTATTTATACCTTGAGGATCAAGGAGGTGAAAGGGGCATTAAGAAAGTTCTAGCAAAGGCTCTGGGAGTA AATATTTTA TGA

[0219] The disclosed GPCR13 polypeptide (SEQ ID NO: 32) encoded protein having 334 amino acid residues is presented in Table 13B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR13 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. The most likely cleavage site for a GPCR13 peptide is between amino acids 61 and 62 at: ILG-NT. TABLE 13B Encoded GPCR13 protein sequence. (SEQ ID NO:32) MCYLSQLCLSLGEHTLHMGMVRHTNESNLAGFILLGFSDYPQLQKVLFVLILILYLLTILGNTTIILVSRLEPKPHM PMYFFLSHLSFLYRCFTSSVIPQLLVNLWEPMKTIAYGGCLVHLYNSHALGSTECVLPALMSCDRYVAVCRPLHYTV LMHIHLCMALASMAWLSGIATTLVQSTLTLQLPFCGHRQVDHFICEVPVLIKLACVGTTFNEAELFVASILFLIVPV SFILVSSGYIAAVLRIKSATGRQKAFGTCFSHLTVVTIFYGTIIFMYLQPAKSRSRDQGKFVSLFYTVVTRMLNPL IYTLRIKEVKGALKKVLAKALGVNIL

[0220] The disclosed GPCR13 amino acid sequence has 178 of 305 amino acid residues (58%) identical to, and 234 of 305 residues (76%) positive with, the Rattus norvegicus (rat) 313 amino acid residue olfatory receptor protein (ptnr: SPTREMBL-ACC:Q63394)(E=2.6e⁻⁹⁶).

[0221] and a T to C SNP at 802 bp of the nucleotide sequence that results in a Leu to Pro change at amino acid 265 of protein sequence.

[0222] Possible SNPs found for GPCR13 are listed in Tables 13C. TABLE 13C SNPs Amino Nucleotide Base Acid Base Position Change Position Change 129 C > G 41 Pro > Ala 309 C > T 101 Leu > Phe 324 T > C 106 Trp > Arg 417 C > G 137 Leu > Val 361 G > A 120 Cys > Tyr 458 C > T Silent N/A 495 G > A 163 Ala > Thr 507 A > G 167 Met > Val 510 G > A 168 Ala > Thr 512 A > G Silent N/A 559 T > C 184 Leu > Pro 765 G > A 253 Gly > Arg 802 T > C 265 Leu > Pro

[0223] The amino acid sequence of GPCR13 has high homology to other proteins as shown in Table 13D. TABLE 13D BLASTX results for GPCR13 Smallest Sum Sequences producing High-scoring High Prob Segment Pairs: Score P (N) Ptnr:SPTREMBL-ACC:Q63394 313 aa . . . 959 2.6e−96 OL1 RECP - Rattus norv,

[0224] The disclosed GPCR13 has homology to the amino acid sequences shown in the BLASTP data listed in Table 13E. TABLE 13E BLASTP results for GPCR13 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|6679170|ref|NP_032 olfactory 312 179/308 232/308 8e−91 788.1| receptor 15 (58%) (75%) [Mus musculus] gi|11177906|ref NP_06 Olfactory 313 178/305 234/305 4e−90 8632.1| receptor (58%) (76%) [Rattus norvegicus] gi|14780900|ref NP_14 olfactory 357 179/305 232/305 2e−89 9046.1| receptor, family (58%) (75%) 2, subfamily B, member 2 [Homo sapiens] gi|12231029|sp|Q15062 OLFACTORY 316 173/303 230/303 4e−89 O2H3 HUMAN RECEPTOR 2H3 (57%) (75%) (OLFACTORY RECEPTOR-LIKE PROTEIN FAT11) gi|15304846|ref XP_05 olfactory 357 178/305 232/305 7e−89 3609.1 receptor, family (58%) (75%) 2, subfamily B, member 2 [Homo sapiens]

[0225] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 13F.

[0226] Table 13G lists the domain description from DOMAIN analysis results against GPCR13. This indicates that the GPCR13 sequence has properties similar to those of other proteins known to contain this domain as well as to the 377 amino acid 7tm domain itself. TABLE 13G Domain Analysis of GPCR13 gnl|Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:112) Length = 254 residues, 94.9% aligned Score = 70.9 bits (172), Expect = 1e−13 GPCR13: 74 KPHMPMYFFLSHLSFLYRCFTSSVIPQLLVNLWEPMKTIAYGGCLVHLYNSHALGSTECV 133 |   || +|+     |  ++ |  |  |           | +        |    + Gn1|Pfam|pfam00001: 14 KLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLVGALFVVNGYASIL 73 GPCR13: 134 LPALMSCDRYVAVCRPLHYTVLMHIHLCMALASMAWLSGIATTLVQSTLTLQLPFCGERQ 193 |   +| |||+|+  || |  +        |  + +  +          | || Gnl|Pfam|pfam00001: 74 LLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALL---------LSLPPLLFSW 124 GPCR13: 194 VDHFIVEVPVLIKLACVGTTFNEAELFVASILFLIVPVSFILVSSGYTAHAV 245 +         +  +     +   + + +++++  ++|+  |||    |   + Gnl|Pfam|pfam00001: 125 LRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRARSQR 184 GPCR13: 246 -LRIKSATGRQKAFGTCFSHLTVVTIFYGTIIFMYL----QPAKSRSRDQGKFVSLFYTV 300  |+ +|++ |+ |       +  +  +    | + |      +  |       ++|+ Gnl|Pfam|pfam00001: 185 SLKRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITLWLAY 244 GPCR13: 201 VTRMLNPLIY 310 |   |||+|| Gnl|Pfam|pfam00001: 245 VNSCLNPIIY 254

[0227] GPCR14

[0228] The disclosed GPCR14 nucleic acid of 996 nucleotides (also referred to as CG50161-03) is shown in Table 13A. The disclosed GPCR14 open reading frame (“ORF”) begins with at nucleotides 12-14 and ending with a TAA codon at nucleotides 993-995. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions, if any, are found upstream from the initiation codon and downstream from the termination codon. TABLE 14A GPCR14 nucleotide sequence. (SEQ ID NO:33) CATGCTGGACT ATGCCCTCTCCATTTACAGGTAGCTCTACTAGAAATATGGAGAGCAGAAACCAATCAACAGTGACT GAATTTATCTTCACTGGATTCCCTCAGCTTCAGGATGGTAGTCTCCTGTACTTCTTTCCTTTACTTTTCATCTATAC TTTTATTATCATTGATAACTTATTAATCTTCTCTGCTGTAAGGCTGGACACCCATCTCCACAACCCCATGTATAATT TTATCAGTATATTTTCCTTTCTGGAGATCTGGTACACCACAGCCACCATTCCCAAGATGCTCTCCAACCTCATCAGT GAAAAGAAGGCCATCTCAATGACTGGCTGCATCTTGCAGATGTATTTCTTCCACTCACTTGAAAACTCAGAGGGGAT CTTGCTGACCACCATGGCCATTGACAGATACGTTGCCATCTGCAACCCTCTTCGCTATCAAATGATCATGACCCCCC GGCTCTGTGCTCAACTCTCTGCAGGTTCCTGCCTCTTCGGTTTCCTTATCCTGCTTCCCGAGATTGTGATGATTTCC ACACTGCCTTTCTGTCGGCCCAACCAAATCCATCAGATCTTCTGTGACTTGGTCCCTGTGCTAAGCCTCGCCTGTAC AGACACGTCCATGATTCTGATTGAGGATGTGATTCATGCTGTGACCATCATCATTACCTTCCTAATCATTGCCCTGT CCTATGTAAGAATTGTCACTGTGATATTGAGGATTCCCTCTTCTGAAGGGAGGCAAAAGGCTTTTTCTACCTGTGCA GGCCACCTCATGGTCTTCCCGATATTCTTTCGCAGTGTATCACTCATGTACTTGCGTTTCAGCGACACTTATCCACC AGTTTTGGACACAGCCATTGCACTGATGTTTACTGTACTTGCTCCATTCTTCAATCCCATCATTTATAGCCTGAGAA ACAAGGACATGAACAATGCGATTAAAAAACTGTTCTGTCTTCAAAAAGTGTTGAACAAGCCTGGAGGTTAA T

[0229] The disclosed GPCR14 of this invention maps to chromosome 1 and the GPCR14 the nucleic acid sequence of this invention has 943 of 945 bases (99%) identical to a gb:GENBANK-ID:AX241804|acc:AX241804.1 mRNA from synthetic construct (Sequence 552 from Patent WO0127158) (E=1.8e⁻²⁰⁶). Chromosome localization information was assigned using OMIM, the electronic northern bioinformatic tool implemented by CuraGen Corporation, public ESTs, public literature references and/or genomic clone homologies. This was executed to derive the chromosomal mapping of the SeqCalling assemblies, Genomic clones, literature references and/or EST sequences that were included in the invention.

[0230] The disclosed GPCR14 polypeptide (SEQ ID NO: 34) encoded protein having 327 amino acid residues is presented in Table 14B using the one-letter amino acid code. The Signal P, Psort and/or Hydropathy results predict that GPCR14 has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.6000. In other embodiments, it is localized at the Golgi body with a certainty of 0.4000, at the endoplasmic reticulum (membrane) with a certainty of 0.3000 or at the endoplasmic reticulum with a certainty of 0.3000. The most likely cleavage site for a GPCR14 peptide is between amino acids 62 and 63, at: AVR-LD. TABLE 14B Encoded GPCR14 protein sequence. (SEQ ID NO:34) MPSPFTGSSTRNMESRNQSTVTEFIFTGFPQLQDGSLLYFFPLLFIYTFIIIDNLLIFSAVRLDTHLHNPMYNFISI FSFLEIWYTTATIPKMLSNLISEKKAISMTGCILQMYFFHSLENSEGILLTTMAIDRYVAICNPLRYQMIMTPRLCA QLSAGSCLFGFLILLPEIVMISTLPFCGPNQIHQIFCDLVPVLSLACTDTSMILIEDVIHAVTIIITFLIIALSYVR IVTVILRIPSSEGRQKAFSTCAGHLMVFPIFFGSVSLMYLRFSDTYPPVLDTAIALMFTVLAPFFNPIIYSLRNKDM NNAIKKLFCLQKVLNKPGG

[0231] The disclosed GPCR14 amino acid sequence of the protein of the invention was found to have 136 of 304 amino acid residues (44%) identical to, and 193 of 304 amino acid residues (63%) similar to, the 321 amino acid residue ptnr:SWISSPROT-ACC:Q9UGF6 protein from Homo sapiens (Human) (Olfactory receptor 5V1 (Hs6M1-21) (E=4.4e⁻⁶⁶).

[0232] GPCR14 is expressed in at least the following tissues: apical microvilli of the retinal pigment epithelium, arterial (aortic), basal forebrain, brain, Burkitt lymphoma cell lines, corpus callosum, cardiac (atria and ventricle), caudate nucleus, CNS and peripheral tissue, cerebellum, cerebral cortex, colon, cortical neurogenic cells, endothelial (coronary artery and umbilical vein) cells, palate epithelia, eye, neonatal eye, frontal cortex, fetal hematopoietic cells, heart, hippocampus, hypothalamus, leukocytes, liver, fetal liver, lung, lung lymphoma cell lines, fetal lymphoid tissue, adult lymphoid tissue, those that express MHC II and III nervous, medulla, subthalamic nucleus, ovary, pancreas, pituitary, placenta, pons, prostate, putamen, serum, skeletal muscle, small intestine, smooth muscle (coronary artery in aortic) spinal cord, spleen, stomach, taste receptor cells of the tongue, testis, thalamus, and thymus tissue. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence.

[0233] The amino acid sequence of GPCR14 has high homology to other proteins as shown in Table 14C. TABLE 14C BLASTX results for GPCR14 Smallest Sum High Prob Sequences producing High-scoring Segment Pairs: Score P(N) ptnr:SWISSPROT-ACC:Q9UGF6 OLF RECP - Homo sapiens, 321 aa . . . 675 4.4e−66

[0234] The disclosed GPCR14 has homology to the amino acid sequences shown in the BLASTP data listed in Table 14D. TABLE 14D BLASTP results for GPCR14 Length Identity Positives Gene Index/Identifier Protein/Organism (aa) (%) (%) Expect gi|13562084|ref|NP_11 olfactory 321 136/304 193/304 8e−60 0503.1| receptor, family (44%) (62%) 5, subfamily V member 1 [Homo sapiens] gi|7242165|ref|NP_035 olfactory 327 132/308 191/308 9e−59 113.1| receptor 41 (42%) (61%) [Mus musculus] gi|12007416|gb|AAG451 m51 olfactory 314 140/303 190/303 1e−58 89.1 receptor (46%) (62%) [Mus musculus] gi|13928994|ref NP_11 olfactory 327 135/308 192/308 2e−58 3898.1 receptor 41 (43%) (61%) [Rattus norvegicus] gi|14596246|emb CAC43 dM538M10.1 (novel 317 135/306 187/306 3e−58 444.1| 7 transmembrane (44%) (60%) receptor (rhodopsin family) (olfactory receptor like) protein similar to human HS6M1-21) [Mus musculus]

[0235] The homology of these sequences is shown graphically in the ClustalW analysis shown in Table 14E.

[0236] Table 14F lists the domain description from DOMAIN analysis results against GPCR14. This indicates that the GPCR14 sequence has properties similar to those of other proteins known to contain this domain as well as to the 377 amino acid 7tm domain itself. TABLE 14F Domain Analysis of GPCR14 gnl, Pfam|pfam00001, 7tm_1, 7 transmembrane receptor (rhodopsin family). (SEQ ID NO:118) Length = 254 residues, 99.6% aligned Score = 97.1 bits (240), Expect = 1e−21 GPCR14: 54 NLLIFSAVLDTHLHNPMYNFISIFSFLEIWYTTATIPKMLSNLISEKKAISMTGCILQM 113 |||+   +     |  |   |+   +  ++ +     |  |  |+          | | Gnl|Pfam|pfam00001: 2 NLLVILVILRTKKLRTPTNIFLLNLAVADLLFLLTLPPWALYYLVGGDWVFGDALCKLVG 61 GPCR14: 114 YFFHSLENSEGILLTTMAIDRYVAICNPLRYQMIMTPRLCAQLSAGSCLFGFLILLPEIV 173   |     +  +||| ++|||||+|| +||||+ | |||    |     +   |+ || ++ Gnl|Pfam|pfam00001: 62 ALFVNGYASILLLTAISIDRYLAIVHPLRYRRIRTPRRAKVLILLVWVLALLLSLPPLL 121 GPCR14: 174 MISTLPFCGPNQIHQIFCDLVPVLSLACTDTSMILIEDVIHAVTIIITFLI-IALSYVRI 232           |    +       +  +    | ++   +   | ++    |   | Gnl|Pfam|pfam00001: 122 FSWLRTVEEGNTTVCLIDFPEESVKRSYVLLSTLVGFVLPLLVILVCYTRILRTLRKRAR 181 GPCR14: 233 VTVILRIPSSEGRQKAFSTCAGHLMVF----PIFFGSVSLMYLRFSDTYPPVLDTAIALM 288     |+  ||  |+ |       ++      |     +       |          | | Gnl|Pfam|pfam00001: 182 SQRSLKRSSSERKAAKMLLVVVVVFVLCWLPYHIVLLLDSLCLLSIWRVLPTALLITLW 241 GPCR14: 289 FTVLAPFFNPIIY 301    +    ||||| Gnl|Pfam|pfam00001: 242 LAYVNSCLNPIIY 254

[0237] The protein similarity information, expression pattern, cellular localization, and map location for the protein and nucleic acid disclosed herein suggest that GPCR 14 may have important structural and/or physiological functions characteristic of the GPCR family. The nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various GPCR- or olfactory receptor (OR)-related pathologies and/or disorders. For example, the compositions of the present invention will have efficacy for the treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders; control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of appetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation, dentatorubro-pallidoluysian atrophy(DRPLA) hypophosphatemic rickets, autosomal dominant (2) acrocallosal syndrome and dyskinesias, such as Huntington's disease.

[0238] The disclosed GPCR14 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated GPCR14 epitope is from about amino acids 5 to 10. In additional embodiments, a GPCR14 epitope is from about amino acids 90 to 95, from about amino acids 130 to 132, from 145 to 150, from 240 to 250, from 310 to 320 and from 330 to 340. The GPCR14 protein also have value in the development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0239] A summary of the GPCRX nucleic acids and proteins of the invention is provided in Table 15. TABLE 15 GPCR Summary Nucle- ic Amino Acid Acid SEQ SEQ Clone:Description ID ID Name Tables of Homolog NO NO GPCR1 1A-1O GPCR1a:SC35113271_(—) 1 2 A_da1 GPCR1b:CG55798-03 3 4 GPCR1c:CG55798-04 5 6 GPCR2  2A-2L  GPCR2a:AC011711_da2 7 8 GPCR2b:CG50147-01 9 10 GPCR3 3A-3H GPCR3:GMAC024428_A_(—) 11 12 (also known as CG92194-01) GPCR4 4A-4F  GPCR4:CG50169-01 13 14 GPCR5 5A-5F  GPCR5:AC009758_da1 15 16 GPCR6 6A-6G GPCR6:CG50149-01 17 18 GPCR7 7A-7H GPCR7:GM_33202597_(—) 19 20 A_da1 GPCR8 8A-8H GPCR8:AC076959_da2 21 22 GPCR9 9A-9G GPCR9:AC073364_da1 23 24 GPCR10 10A-10G GPCR10:CG55732-01 25 26 GPCR11 11A-11G GPCR11:sggc_draft_(—) 27 28 ba656o22_20000731_da1 GPCR12 12A-12G GPCR12:ba407h12_da1 29 30 GPCR13 13A-13G GPCR13:AC074365_da1 31 32 GPCR14 14A-14F  GPCR14:CG50161-03 33 34

[0240] GPCRX Nucleic Acids and Polypeptides

[0241] One aspect of the invention pertains to isolated nucleic acid molecules that encode GPCRX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify GPCRX-encoding nucleic acids (e.g., GPCRX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of GPCRX nucleic acid molecules. As used herein, the term “nucleic acid molecule” is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.

[0242] An GPCRX nucleic acid can encode a mature GPCRX polypeptide. As used herein, a “mature” form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product “mature” form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a “mature” form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a “mature” form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristoylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

[0243] The term “probes”, as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

[0244] The term “isolated” nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an “isolated” nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5′- and 3′-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated GPCRX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.

[0245] A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 as a hybridization probe, GPCRX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2^(nd) Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993.)

[0246] A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to GPCRX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0247] As used herein, the term “oligonucleotide” refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

[0248] In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of an GPCRX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 is one that is sufficiently complementary to the nucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 that it can hydrogen bond with little or no mismatches to the nucleotide sequence shown SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, thereby forming a stable duplex.

[0249] As used herein, the term “complementary” refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term “binding” means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

[0250] Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.

[0251] Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993, and below.

[0252] A “homologous nucleic acid sequence” or “homologous amino acid sequence, ” or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of GPCRX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for an GPCRX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human GPCRX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, as well as a polypeptide possessing GPCRX biological activity. Various biological activities of the GPCRX proteins are described below.

[0253] An GPCRX polypeptide is encoded by the open reading frame (“ORF”) of an GPCRX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG “start” codon and terminates with one of the three “stop” codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonafide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

[0254] The nucleotide sequences determined from the cloning of the human GPCRX genes allows for the generation of probes and primers designed for use in identifying and/or cloning GPCRX homologues in other cell types, e.g. from other tissues, as well as GPCRX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33; or an anti-sense strand nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33; or of a naturally occurring mutant of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33.

[0255] Probes based on the human GPCRX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express an GPCRX protein, such as by measuring a level of an GPCRX-encoding nucleic acid in a sample of cells from a subject e.g., detecting GPCRX mRNA levels or determining whether a genomic GPCRX gene has been mutated or deleted.

[0256] “A polypeptide having a biologically-active portion of an GPCRX polypeptide” refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a “biologically-active portion of GPCRX” can be prepared by isolating a portion SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 that encodes a polypeptide having an GPCRX biological activity (the biological activities of the GPCRX proteins are described below), expressing the encoded portion of GPCRX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of GPCRX.

[0257] GPCRX Nucleic Acid and Polypeptide Variants

[0258] The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences shown SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 due to degeneracy of the genetic code and thus encode the same GPCRX proteins as that encoded by the nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. In addition to the human GPCRX nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the GPCRX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the GPCRX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms “gene” and “recombinant gene” refer to nucleic acid molecules comprising an open reading frame (ORF) encoding an GPCRX protein, preferably a vertebrate GPCRX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the GPCRX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the GPCRX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the GPCRX polypeptides, are intended to be within the scope of the invention.

[0259] Moreover, nucleic acid molecules encoding GPCRX proteins from other species, and thus that have a nucleotide sequence that differs from the human sequence SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the GPCRX cDNAs of the invention can be isolated based on their homology to the human GPCRX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

[0260] Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33.

[0261] In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.

[0262] Homologs (i.e., nucleic acids encoding GPCRX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

[0263] As used herein, the phrase “stringent hybridization conditions” refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60° C. for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

[0264] Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C., followed by one or more washes in 0.2×SSC, 0.01% BSA at 50° C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 corresponds to a naturally-occurring nucleic acid molecule. As used herein, a “naturally-occurring” nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

[0265] In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55° C., followed by one or more washes in 1×SSC, 0.1% SDS at 37° C. Other conditions of moderate stringency that maybe used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Knegler, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

[0266] In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40° C., followed by one or more washes in 2×SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50° C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

[0267] Conservative Mutations

[0268] In addition to naturally-occurring allelic variants of GPCRX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 thereby leading to changes in the amino acid sequences of the encoded GPCRX proteins, without altering the functional ability of said GPCRX proteins. For example, nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues can be made in the sequence of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequences of the GPCRX proteins without altering their biological activity, whereas an “essential” amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the GPCRX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.

[0269] Another aspect of the invention pertains to nucleic acid molecules encoding GPCRX proteins that contain changes in amino acid residues that are not essential for activity. Such GPCRX proteins differ in amino acid sequence from SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to the amino acid sequences of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NOS: SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; more preferably at least about 70% homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; still more preferably at least about 80% homologous to SEQ ID NOS: SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; even more preferably at least about 90% homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; and most preferably at least about 95% homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34.

[0270] An isolated nucleic acid molecule encoding an GPCRX protein homologous to the protein of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.

[0271] Mutations can be introduced into SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the GPCRX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an GPCRX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for GPCRX biological activity to identify mutants that retain activity. Following mutagenesis of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.

[0272] The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved “strong” residues or fully conserved “weak” residues. The “strong” group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the “weak” group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letters within each group represent the single letter amino acid code.

[0273] In one embodiment, a mutant GPCRX protein can be assayed for (i) the ability to form protein:protein interactions with other GPCRX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant GPCRX protein and an GPCRX ligand; or (iii) the ability of a mutant GPCRX protein to bind to an intracellular target protein or biologically-active portion thereof, (e.g. avidin proteins).

[0274] In yet another embodiment, a mutant GPCRX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

[0275] Antisense Nucleic Acids

[0276] Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or fragments, analogs or derivatives thereof. An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire GPCRX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of an GPCRX protein of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or antisense nucleic acids complementary to an GPCRX nucleic acid sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, are additionally provided.

[0277] In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence encoding an GPCRX protein. The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence encoding the GPCRX protein. The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).

[0278] Given the coding strand sequences encoding the GPCRX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of GPCRX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of GPCRX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of GPCRX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g. an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used).

[0279] Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0280] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an GPCRX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0281] In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (see, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (see, e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.

[0282] Ribozymes and PNA Moieties

[0283] Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

[0284] In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave GPCRX mRNA transcripts to thereby inhibit translation of GPCRX mRNA. A ribozyme having specificity for an GPCRX-encoding nucleic acid can be designed based upon the nucleotide sequence of an GPCRX cDNA disclosed herein (i.e., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an GPCRX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al. and U.S. Pat. No. 5,116,742 to Cech, et al. GPCRX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.

[0285] Alternatively, GPCRX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the GPCRX nucleic acid (e.g., the GPCRX promoter and/or enhancers) to form triple helical structures that prevent transcription of the GPCRX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

[0286] In various embodiments, the GPCRX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

[0287] PNAs of GPCRX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of GPCRX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S₁ nucleases (see, Hyrup, et al., 1996.supra); or as probes or primers for DNA sequence and hybridization (see, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra).

[0288] In another embodiment, PNAs of GPCRX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of GPCRX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5: 1119-11124.

[0289] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a bybridization-triggered cleavage agent, and the like.

[0290] GPCRX Polypeptides

[0291] A polypeptide according to the invention includes a polypeptide including the amino acid sequence of GPCRX polypeptides whose sequences are provided in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 while still encoding a protein that maintains its GPCRX activities and physiological functions, or a functional fragment thereof.

[0292] In general, an GPCRX variant that preserves GPCRX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

[0293] One aspect of the invention pertains to isolated GPCRX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-GPCRX antibodies. In one embodiment, native GPCRX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, GPCRX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, an GPCRX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

[0294] An “isolated” or “purified” polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the GPCRX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of GPCRX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language “substantially free of cellular material” includes preparations of GPCRX proteins having less than about 30% (by dry weight) of non-GPCRX proteins (also referred to herein as a “contaminating protein”), more preferably less than about 20% of non-GPCRX proteins, still more preferably less than about 10% of non-GPCRX proteins, and most preferably less than about 5% of non-GPCRX proteins. When the GPCRX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the GPCRX protein preparation.

[0295] The language “substantially free of chemical precursors or other chemicals” includes preparations of GPCRX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of GPCRX proteins having less than about 30% (by dry weight) of chemical precursors or non-GPCRX chemicals, more preferably less than about 20% chemical precursors or non-GPCRX chemicals, still more preferably less than about 10% chemical precursors or non-GPCRX chemicals, and most preferably less than about 5% chemical precursors or non-GPCRX chemicals.

[0296] Biologically-active portions of GPCRX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the GPCRX proteins (e.g., the amino acid sequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34) that include fewer amino acids than the fall-length GPCRX proteins, and exhibit at least one activity of an GPCRX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the GPCRX protein. A biologically-active portion of an GPCRX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

[0297] Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native GPCRX protein.

[0298] In an embodiment, the GPCRX protein has an amino acid sequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34. In other embodiments, the GPCRX protein is substantially homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, and retains the functional activity of the protein of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the GPCRX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, and retains the functional activity of the GPCRX proteins of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34.

[0299] Determining Homology Between Two or More Sequences

[0300] To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid “homology” is equivalent to amino acid or nucleic acid “identity”).

[0301] The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33.

[0302] The term “sequence identity” refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term “substantial identity” as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

[0303] Chimeric and Fusion Proteins

[0304] The invention also provides GPCRX chimeric or fusion proteins. As used herein, an GPCRX “chimeric protein” or “fusion protein” comprises an GPCRX polypeptide operatively-linked to a non-GPCRX polypeptide. An “GPCRX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to an GPCRX protein (SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34), whereas a “non-GPCRX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the GPCRX protein, e.g., a protein that is different from the GPCRX protein and that is derived from the same or a different organism. Within an GPCRX fusion protein the GPCRX polypeptide can correspond to all or a portion of an GPCRX protein. In one embodiment, an GPCRX fusion protein comprises at least one biologically-active portion of an GPCRX protein. In another embodiment, an GPCRX fusion protein comprises at least two biologically-active portions of an GPCRX protein. In yet another embodiment, an GPCRX fusion protein comprises at least three biologically-active portions of an GPCRX protein. Within the fusion protein, the term “operatively-linked” is intended to indicate that the GPCRX polypeptide and the non-GPCRX polypeptide are fused in-frame with one another. The non-GPCRX polypeptide can be fused to the N-terminus or C-terminus of the GPCRX polypeptide.

[0305] In one embodiment, the fusion protein is a GST-GPCRX fusion protein in which the GPCRX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant GPCRX polypeptides.

[0306] In another embodiment, the fusion protein is an GPCRX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of GPCRX can be increased through use of a heterologous signal sequence.

[0307] In yet another embodiment, the fusion protein is an GPCRX-immunoglobulin fusion protein in which the GPCRX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The GPCRX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between an GPCRX ligand and an GPCRX protein on the surface of a cell, to thereby suppress GPCRX-mediated signal transduction in vivo. The GPCRX-immunoglobulin fusion proteins can be used to affect the bioavailability of an GPCRX cognate ligand. Inhibition of the GPCRX ligand/GPCRX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the GPCRX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-GPCRX antibodies in a subject, to purify GPCRX ligands, and in screening assays to identify molecules that inhibit the interaction of GPCRX with an GPCRX ligand.

[0308] An GPCRX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). An GPCRX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the GPCRX protein.

[0309] GPCRX Agonists and Antagonists

[0310] The invention also pertains to variants of the GPCRX proteins that function as either GPCRX agonists (i.e., mimetics) or as GPCRX antagonists. Variants of the GPCRX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the GPCRX protein). An agonist of the GPCRX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the GPCRX protein. An antagonist of the GPCRX protein can inhibit one or more of the activities of the naturally occurring form of the GPCRX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the GPCRX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the GPCRX proteins.

[0311] Variants of the GPCRX proteins that function as either GPCRX agonists (i.e., mimetics) or as GPCRX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the GPCRX proteins for GPCRX protein agonist or antagonist activity. In one embodiment, a variegated library of GPCRX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of GPCRX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential GPCRX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of GPCRX sequences therein. There are a variety of methods which can be used to produce libraries of potential GPCRX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential GPCRX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477.

[0312] Polypeptide Libraries

[0313] In addition, libraries of fragments of the GPCRX protein coding sequences can be used to generate a variegated population of GPCRX fragments for screening and subsequent selection of variants of an GPCRX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of an GPCRX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with SI nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the GPCRX proteins.

[0314] Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of GPCRX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify GPCRX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331.

[0315] Anti-GPCRX Antibodies

[0316] Also included in the invention are antibodies to GPCRX proteins, or fragments of GPCRX proteins. The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, F_(ab′) and F_((ab′)2) fragments, and an F_(ab) expression library. In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG₁, IgG₂, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

[0317] An isolated GPCRX-related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

[0318] In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of GPCRX-related protein that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human GPCRX-related protein sequence will indicate which regions of a GPCRX-related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each of which is incorporated herein by reference in its entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0319] A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

[0320] Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow and Lane, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below.

[0321] Polyclonal Antibodies

[0322] For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

[0323] The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).

[0324] Monoclonal Antibodies

[0325] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

[0326] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

[0327] The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, MONOCLONAL ANTIBODIES: PRINCIPLES AND PRACTICE, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

[0328] Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., MONOCLONAL ANTIBODY PRODUCTION TECHNIQUES AND APPLICATIONS, Marcel Dekker, Inc., New York, (1987) pp. 51-63).

[0329] The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.

[0330] After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.

[0331] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0332] The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

[0333] Humanized Antibodies

[0334] The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Pat. No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Strect. Biol., 2:593-596 (1992)).

[0335] Human Antibodies

[0336] Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies”, or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).

[0337] Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

[0338] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

[0339] A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat. No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

[0340] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

[0341] F_(ab) Fragments and Single Chain Antibodies

[0342] According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted for the construction of F_(ab) expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_(ab) fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F_((ab′)2) fragment produced by pepsin digestion of an antibody molecule; (ii) an F_(ab) fragment generated by reducing the disulfide bridges of an F_((ab′)2) fragment; (iii) an F_(ab) fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F_(v) fragments.

[0343] Bispecific Antibodies

[0344] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit. Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., 1991 EMBO J., 10:3655-3659.

[0345] Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

[0346] According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0347] Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)₂ molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

[0348] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (V_(H)) connected to a light-chain variable domain (V_(L)) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V_(H) and V_(L) domains of one fragment are forced to pair with the complementary V_(L) and V_(H) domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain F_(v) (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).

[0349] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0350] Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

[0351] Heteroconjugate Antibodies

[0352] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

[0353] Effector Function Engineering

[0354] It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

[0355] Immunoconjugates

[0356] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

[0357] Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, a pha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y, and ¹⁸⁶Re.

[0358] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

[0359] In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

[0360] In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme-linked immunosorbent assay (ELISA) and other immunologically-mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an GPCRX protein is facilitated by generation of hybridomas that bind to the fragment of an GPCRX protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an GPCRX protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0361] Anti-GPCRX antibodies may be used in methods known within the art relating to the localization and/or quantitation of an GPCRX protein (e.g., for use in measuring levels of the GPCRX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies for GPCRX proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antibody derived binding domain, are utilized as pharmacologically-active compounds (hereinafter “Therapeutics”).

[0362] An anti-GPCRX antibody (e.g., monoclonal antibody) can be used to isolate an GPCRX polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. An anti-GPCRX antibody can facilitate the purification of natural GPCRX polypeptide from cells and of recombinantly-produced GPCRX polypeptide expressed in host cells. Moreover, an anti-GPCRX antibody can be used to detect GPCRX protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the GPCRX protein. Anti-GPCRX antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g. to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

[0363] GPCRX Recombinant Expression Vectors and Host Cells

[0364] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding an GPCRX protein, or derivatives, fragments, analogs or bomologs thereof. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as “expression vectors”. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0365] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

[0366] The term “regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., GPCRX proteins, mutant forms of GPCRX proteins, fusion proteins, etc.).

[0367] The recombinant expression vectors of the invention can be designed for expression of GPCRX proteins in prokaryotic or eukaryotic cells. For example, GPCRX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0368] Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 3140), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0369] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

[0370] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

[0371] In another embodiment, the GPCRX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kuijan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.). Alternatively, GPCRX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

[0372] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

[0373] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Baneiji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264, 166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

[0374] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to GPCRX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al., “Antisense RNA as a molecular tool for genetic analysis, ” Reviews-Trends in Genetics, Vol. 1(1) 1986.

[0375] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

[0376] A host cell can be any prokaryotic or eukaryotic cell. For example, GPCRX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0377] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

[0378] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding GPCRX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0379] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) GPCRX protein. Accordingly, the invention further provides methods for producing GPCRX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding GPCRX protein has been introduced) in a suitable medium such that GPCRX protein is produced. In another embodiment, the method further comprises isolating GPCRX protein from the medium or the host cell.

[0380] Transgenic GPCRX Animals

[0381] The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which GPCRX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous GPCRX sequences have been introduced into their genome or homologous recombinant animals in which endogenous GPCRX sequences have been altered. Such animals are useful for studying the function and/or activity of GPCRX protein and for identifying and/or evaluating modulators of GPCRX protein activity. As used herein, a “transgenic animal” is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a “homologous recombinant animal” is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous GPCRX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0382] A transgenic animal of the invention can be created by introducing GPCRX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human GPCRX cDNA sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human GPCRX gene, such as a mouse GPCRX gene, can be isolated based on hybridization to the human GPCRX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the GPCRX transgene to direct expression of GPCRX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the GPCRX transgene in its genome and/or expression of GPCRX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding GPCRX protein can further be bred to other transgenic animals carrying other transgenes.

[0383] To create a homologous recombinant animal, a vector is prepared which contains at least a portion of an GPCRX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the GPCRX gene. The GPCRX gene can be a human gene (e.g., the cDNA of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33), but more preferably, is a non-human homologue of a human GPCRX gene. For example, a mouse homologue of human GPCRX gene of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 can be used to construct a homologous recombination vector suitable for altering an endogenous GPCRX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous GPCRX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a “knock out” vector).

[0384] Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous GPCRX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous GPCRX protein). In the homologous recombination vector, the altered portion of the GPCRX gene is flanked at its 5′- and 3′-termini by additional nucleic acid of the GPCRX gene to allow for homologous recombination to occur between the exogenous GPCRX gene carried by the vector and an endogenous GPCRX gene in an embryonic stem cell. The additional flanking GPCRX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5′- and 3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced GPCRX gene has homologously-recombined with the endogenous GPCRX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915.

[0385] The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

[0386] In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0387] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G₀ phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.

[0388] Pharmaceutical Compositions

[0389] The GPCRX nucleic acid molecules, GPCRX proteins, and anti-GPCRX antibodies (also referred to herein as “active compounds”) of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0390] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0391] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0392] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., an GPCRX protein or anti-GPCRX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0393] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0394] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0395] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0396] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0397] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0398] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0399] The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

[0400] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0401] Screening and Detection Methods

[0402] The isolated nucleic acid molecules of the invention can be used to express GPCRX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect GPCRX mRNA (e.g., in a biological sample) or a genetic lesion in an GPCRX gene, and to modulate GPCRX activity, as described further, below. In addition, the GPCRX proteins can be used to screen drugs or compounds that modulate the GPCRX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of GPCRX protein or production of GPCRX protein forms that have decreased or aberrant activity compared to GPCRX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-GPCRX antibodies of the invention can be used to detect and isolate GPCRX proteins and modulate GPCRX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

[0403] The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

[0404] Screening Assays

[0405] The invention provides a method (also referred to herein as a “screening assay”) for identifying modulators, i. e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to GPCRX proteins or have a stimulatory or inhibitory effect on, e.g., GPCRX protein expression or GPCRX protein activity. The invention also includes compounds identified in the screening assays described herein.

[0406] In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of an GPCRX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the “one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12:145.

[0407] A “small molecule” as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

[0408] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37:1233.

[0409] Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat. No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0410] In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of GPCRX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to an GPCRX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the GPCRX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the GPCRX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of GPCRX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds GPCRX to form an assay mixture, contacting the assay mixture with a test recompound, and determining the ability of the test compound to interact with an GPCRX protein, wherein determining the ability of the test compound to interact with an GPCRX protein comprises determining the ability of the test compound to preferentially bind to GPCRX protein or a biologically-active portion thereof as compared to the known compound.

[0411] In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of GPCRX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the GPCRX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of GPCRX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the GPCRX protein to bind to or interact with an GPCRX target molecule. As used herein, a “target molecule” is a molecule with which an GPCRX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses an GPCRX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. An GPCRX target molecule can be a non-GPCRX molecule or an GPCRX protein or polypeptide of the invention. In one embodiment, an GPCRX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound GPCRX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with GPCRX.

[0412] Determining the ability of the GPCRX protein to bind to or interact with an GPCRX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the GPCRX protein to bind to or interact with an GPCRX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca²⁺, diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising an GPCRX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

[0413] In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting an GPCRX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the GPCRX protein or biologically-active portion thereof. Binding of the test compound to the GPCRX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the GPCRX protein or biologically-active portion thereof with a known compound which binds GPCRX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an GPCRX protein, wherein determining the ability of the test compound to interact with an GPCRX protein comprises determining the ability of the test compound to preferentially bind to GPCRX or biologically-active portion thereof as compared to the known compound.

[0414] In still another embodiment, an assay is a cell-free assay comprising contacting GPCRX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the GPCRX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of GPCRX can be accomplished, for example, by determining the ability of the GPCRX protein to bind to an GPCRX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of GPCRX protein can be accomplished by determining the ability of the GPCRX protein further modulate an GPCRX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.

[0415] In yet another embodiment, the cell-free assay comprises contacting the GPCRX protein or biologically-active portion thereof with a known compound which binds GPCRX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an GPCRX protein, wherein determining the ability of the test compound to interact with an GPCRX protein comprises determining the ability of the GPCRX protein to preferentially bind to or modulate the activity of an GPCRX target molecule.

[0416] The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of GPCRX protein. In the case of cell-free assays comprising the membrane-bound form of GPCRX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of GPCRX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)_(n), N-dodecyl--N, N-dimethyl-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).

[0417] In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either GPCRX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to GPCRX protein, or interaction of GPCRX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-GPCRX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or GPCRX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of GPCRX protein binding or activity determined using standard techniques.

[0418] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the GPCRX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated GPCRX protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with GPCRX protein or target molecules, but which do not interfere with binding of the GPCRX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or GPCRX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the GPCRX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the GPCRX protein or target molecule.

[0419] In another embodiment, modulators of GPCRX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of GPCRX mRNA or protein in the cell is determined. The level of expression of GPCRX mRNA or protein in the presence of the candidate compound is compared to the level of expression of GPCRX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of GPCRX mRNA or protein expression based upon this comparison. For example, when expression of GPCRX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of GPCRX mRNA or protein expression. Alternatively, when expression of GPCRX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of GPCRX mRNA or protein expression. The level of GPCRX mRNA or protein expression in the cells can be determined by methods described herein for detecting GPCRX mRNA or protein.

[0420] In yet another aspect of the invention, the GPCRX proteins can be used as “bait proteins” in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with GPCRX (“GPCRX-binding proteins” or “GPCRX-bp”) and modulate GPCRX activity. Such GPCRX-binding proteins are also likely to be involved in the propagation of signals by the GPCRX proteins as, for example, upstream or downstream elements of the GPCRX pathway.

[0421] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for GPCRX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming an GPCRX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with GPCRX.

[0422] The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

[0423] Detection Assays

[0424] Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

[0425] Chromosome Mapping

[0426] Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the GPCRX sequences, SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or fragments or derivatives thereof, can be used to map the location of the GPCRX genes, respectively, on a chromosome. The mapping of the GPCRX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

[0427] Briefly, GPCRX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the GPCRX sequences. Computer analysis of the GPCRX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the GPCRX sequences will yield an amplified fragment.

[0428] Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

[0429] PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the GPCRX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes. Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

[0430] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

[0431] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325: 783-787.

[0432] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the GPCRX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

[0433] Tissue Typing

[0434] The GPCRX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP (“restriction fragment length polymorphisms, ” described in U.S. Pat. No. 5,272,057).

[0435] Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the GPCRX sequences described herein can be used to prepare two PCR primers from the 5′- and 3′-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

[0436] Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The GPCRX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

[0437] Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33 are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

[0438] Predictive Medicine

[0439] The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining GPCRX protein and/or nucleic acid expression as well as GPCRX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant GPCRX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with GPCRX protein, nucleic acid expression or activity. For example, mutations in an GPCRX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with GPCRX protein, nucleic acid expression, or biological activity.

[0440] Another aspect of the invention provides methods for determining GPCRX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as “pharmacogenomics”). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.)

[0441] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of GPCRX in clinical trials.

[0442] These and other agents are described in further detail in the following sections.

[0443] Diagnostic Assays

[0444] An exemplary method for detecting the presence or absence of GPCRX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting GPCRX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes GPCRX protein such that the presence of GPCRX is detected in the biological sample. An agent for detecting GPCRX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to GPCRX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length GPCRX nucleic acid, such as the nucleic acid of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to GPCRX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

[0445] An agent for detecting GPCRX protein is an antibody capable of binding to GPCRX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g. Fab or F(ab′)₂) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect GPCRX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of GPCRX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of GPCRX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of GPCRX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of GPCRX protein include introducing into a subject a labeled anti-GPCRX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0446] In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

[0447] In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting GPCRX protein, mRNA, or genomic DNA, such that the presence of GPCRX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of GPCRX protein, mRNA or genomic DNA in the control sample with the presence of GPCRX protein, mRNA or genomic DNA in the test sample.

[0448] The invention also encompasses kits for detecting the presence of GPCRX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting GPCRX protein or mRNA in a biological sample; means for determining the amount of GPCRX in the sample; and means for comparing the amount of GPCRX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect GPCRX protein or nucleic acid.

[0449] Prognostic Assays

[0450] The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant GPCRX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with GPCRX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant GPCRX expression or activity in which a test sample is obtained from a subject and GPCRX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of GPCRX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant GPCRX expression or activity. As used herein, a “test sample” refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

[0451] Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant GPCRX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant GPCRX expression or activity in which a test sample is obtained and GPCRX protein or nucleic acid is detected (e.g., wherein the presence of GPCRX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant GPCRX expression or activity).

[0452] The methods of the invention can also be used to detect genetic lesions in an GPCRX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding an GPCRX-protein, or the misexpression of the GPCRX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from an GPCRX gene; (ii) an addition of one or more nucleotides to an GPCRX gene; (iii) a substitution of one or more nucleotides of an GPCRX gene, (iv) a chromosomal rearrangement of an GPCRX gene; (v) an alteration in the level of a messenger RNA transcript of an GPCRX gene, (vi) aberrant modification of an GPCRX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of an GPCRX gene, (viii) a non-wild-type level of an GPCRX protein, (ix) allelic loss of an GPCRX gene, and (x) inappropriate post-translational modification of an GPCRX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in an GPCRX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0453] In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4, 683, 202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the GPCRX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to an GPCRX gene under conditions such that hybridization and amplification of the GPCRX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

[0454] Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

[0455] In an alternative embodiment, mutations in an GPCRX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat. No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

[0456] In other embodiments, genetic mutations in GPCRX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in GPCRX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

[0457] In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the GPCRX gene and detect mutations by comparing the sequence of the sample GPCRX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g. PCT International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl. Biochem. Biotechnol. 38: 147-159).

[0458] Other methods for detecting mutations in the GPCRX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of “mismatch cleavage” starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type GPCRX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S₁ nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al., 1988. Proc. NatL Acad. Sci. USA 85: 4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.

[0459] In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called “DNA mismatch repair” enzymes) in defined systems for detecting and mapping point mutations in GPCRX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on an GPCRX sequence, e.g., a wild-type GPCRX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Pat. No. 5,459,039. In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in GPCRX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control GPCRX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7: 5.

[0460] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.

[0461] Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

[0462] Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3′-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3′-terminus of the 5′ sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

[0463] The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving an GPCRX gene.

[0464] Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which GPCRX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0465] Pharmacogenomics

[0466] Agents, or modulators that have a stimulatory or inhibitory effect on GPCRX activity (e.g., GPCRX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of GPCRX protein, expression of GPCRX nucleic acid, or mutation content of GPCRX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

[0467] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0468] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

[0469] Thus, the activity of GPCRX protein, expression of GPCRX nucleic acid, or mutation content of GPCRX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with an GPCRX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

[0470] Monitoring of Effects During Clinical Trials

[0471] Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of GPCRX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase GPCRX gene expression, protein levels, or upregulate GPCRX activity, can be monitored in clinical trails of subjects exhibiting decreased GPCRX gene expression, protein levels, or downregulated GPCRX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease GPCRX gene expression, protein levels, or downregulate GPCRX activity, can be monitored in clinical trails of subjects exhibiting increased GPCRX gene expression, protein levels, or upregulated GPCRX activity. In such clinical trials, the expression or activity of GPCRX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a “read out” or markers of the immune responsiveness of a particular cell.

[0472] By way of example, and not of limitation, genes, including GPCRX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates GPCRX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of GPCRX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of GPCRX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

[0473] In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of an GPCRX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the GPCRX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the GPCRX protein, mRNA, or genomic DNA in the pre-administration sample with the GPCRX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of GPCRX to higher levels than detected, ie., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of GPCRX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

[0474] Methods of Treatment

[0475] The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant GPCRX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright hereditary ostoeodystrophy, and other diseases, disorders and conditions of the like.

[0476] These methods of treatment will be discussed more fully, below.

[0477] Disease and Disorders

[0478] Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are “dysfunctional” (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to “knockout” endoggenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators (i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

[0479] Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

[0480] Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

[0481] Prophylactic Methods

[0482] In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant GPCRX expression or activity, by administering to the subject an agent that modulates GPCRX expression or at least one GPCRX activity. Subjects at risk for a disease that is caused or contributed to by aberrant GPCRX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the GPCRX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of GPCRX aberrancy, for example, an GPCRX agonist or GPCRX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

[0483] Therapeutic Methods

[0484] Another aspect of the invention pertains to methods of modulating GPCRX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of GPCRX protein activity associated with the cell. An agent that modulates GPCRX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of an GPCRX protein, a peptide, an GPCRX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more GPCRX protein activity. Examples of such stimulatory agents include active GPCRX protein and a nucleic acid molecule encoding GPCRX that has been introduced into the cell. In another embodiment, the agent inhibits one or more GPCRX protein activity. Examples of such inhibitory agents include antisense GPCRX nucleic acid molecules and anti-GPCRX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of an GPCRX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) GPCRX expression or activity. In another embodiment, the method involves administering an GPCRX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant GPCRX expression or activity.

[0485] Stimulation of GPCRX activity is desirable in situations in which GPCRX is abnormally downregulated and/or in which increased GPCRX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

[0486] Determination of the Biological Effect of the Therapeutic

[0487] In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.

[0488] In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

[0489] Prophylactic and Therapeutic Uses of the Compositions of the Invention

[0490] The GPCRX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's disease, Parkinson's disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

[0491] As an example, a cDNA encoding the GPCRX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's disease, Parkinson's disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.

[0492] Both the novel nucleic acid encoding the GPCRX protein, and the GPCRX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

[0493] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES Example 1

[0494] Identification of GPCRX Nucleic Acids

[0495] TblastN using CuraGen Corporation's sequence file for polypeptides or homologs was run against the Genomic Daily Files made available by GenBank or from files downloaded from the individual sequencing centers. Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

[0496] The novel GPCRX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. PCR primer sequences were used for obtaining different clones. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

[0497] Physical clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

Example 2

[0498] Identification of Single Nucleotide Polymorphisms in NOVX Nucleic Acid Sequences

[0499] Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

[0500] SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.

[0501] Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed.

[0502] The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence.

Example 3

[0503] Quantitative Expression Analysis of Clones in Various Cells and Tissues

[0504] The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoinflammatory diseases), Panel CNSD.01 (containing samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains).

[0505] RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

[0506] First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

[0507] In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42° C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using 1X TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

[0508] Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration=250 nM, primer melting temperature (Tm) range=58°-60° C., primer optimal Tm=59° C., maximum primer difference=2° C., probe does not have 5′G, probe Tm must be 10° C. greater than primer Tm, amplicon size 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, Tex., USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5′ and 3′ ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900 nM each, and probe, 200 nM.

[0509] PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48° C. for 30 minutes followed by amplification/PCR cycles as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

[0510] When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using 1×TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were analyzed and processed as described previously.

[0511] Panels 1, 1.1, 1.2, and 1.3D

[0512] The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

[0513] In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used:

[0514] ca.=carcinoma,

[0515] *=established from metastasis,

[0516] met=metastasis,

[0517] s cell var=small cell variant,

[0518] non-s=non-sm=non-small,

[0519] squam=squamous,

[0520] pl. eff=pl effusion=pleural effusion,

[0521] glio=glioma,

[0522] astro=astrocytoma, and

[0523] neuro=neuroblastoma.

[0524] General_Screening_Panel_v1.4

[0525] The plates for Panel 1.4 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panel 1.4 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panel 1.4 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

[0526] Panels 2D and 2.2

[0527] The plates for Panels 2D and 2.2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have “matched margins” obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted “NAT” in the results below. The tumor tissue and the “matched margins” are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, Calif.), Research Genetics, and Invitrogen.

[0528] Panel 3D

[0529] The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature.

[0530] Panels 4D, 4R, and 4.1D

[0531] Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, Calif.) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, Calif.). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, Pa.).

[0532] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5ng/ml, TNF alpha at approximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4 at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 at approximately 5-10 ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

[0533] Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 1 00 M non essential amino acids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20 ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at 20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100 gM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final concentration of approximately 2×10⁶ cells/ml in DMEM 5% FCS (Hyclone), 100 gM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5×10⁵M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1-7 days for RNA preparation.

[0534] Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50 ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 μg/ml for 6 and 12-14 hours.

[0535] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) and plated at 10⁶cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5 μg/ml anti-CD28 (Pharmingen) and 3 μg/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

[0536] To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁻⁵M (Gibco), and 10 mM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10 ng/ml. Cells were harvested for RNA preparation at 24, 48 and 72 hours.

[0537] To prepare the primary and secondary Th1/Th2 and Tr1 cells, six-well Falcon plates were coated overnight with 10 μg/ml anti-CD28 (Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.) were cultured at 10⁵-10⁶cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4 ng/ml). IL-12 (5ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Th1, while IL-4 (5 ng/ml) and anti-IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5 days, the activated Th1, Th2 and Tr1 lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Th1, Th2 and Tr1 lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

[0538] The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in 0.1 mM dbcAMP at 5×10⁻⁵ cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5×10⁻⁵ cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

[0539] For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷ cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15 ml Falcon Tube. An equal volume of isopropanol was added and left at −20° C. overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300 μl of RNAse-free water and 35 μl buffer (Promega) 5 μl DTT, 7 μl RNAsin and 8 μl DNAse were added. The tube was incubated at 37° C. for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at −80° C.

[0540] AI_comprehensive panel_v1.0

[0541] The plates for AI_comprehensive panel_v1.0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, Md.). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

[0542] Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

[0543] Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.

[0544] Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

[0545] Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-i anti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

[0546] In the labels employed to identify tissues in the AI_comprehensive panel_v1.0 panel, the following abbreviations are used:

[0547] AI=Autoimmunity

[0548] Syn=Synovial

[0549] Normal=No apparent disease

[0550] Rep22/Rep20=individual patients

[0551] RA=Rheumatoid arthritis

[0552] Backus=From Backus Hospital

[0553] OA=Osteoarthritis

[0554] (SS) (BA) (MF)=Individual patients

[0555] Adj=Adjacent tissue

[0556] Match control=adjacent tissues

[0557] -M=Male

[0558] -F=Female

[0559] COPD=Chronic obstructive pulmonary disease

[0560] Panels 5D and 51

[0561] The plates for Panel 5D and 5I include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

[0562] In the Gestational Diabetes study subjects are young (18-40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample.

[0563] Patient 2: Diabetic Hispanic, overweight, not on insulin

[0564] Patient 7-9: Nondiabetic Caucasian and obese (BMI>30)

[0565] Patient 10: Diabetic Hispanic, overweight, on insulin

[0566] Patient 11: Nondiabetic African American and overweight

[0567] Patient 12: Diabetic Hispanic on insulin

[0568] Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr. 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

[0569] Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose

[0570] Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

[0571] Donor 2 and 3 AD: Adipose, Adipose Differentiated

[0572] Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

[0573] Panel 5I contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 5I.

[0574] In the labels employed to identify tissues in the 5D and 5I panels, the following abbreviations are used:

[0575] GO Adipose=Greater Omentum Adipose

[0576] SK=Skeletal Muscle

[0577] UT=Uterus

[0578] PL=Placenta

[0579] AD=Adipose Differentiated

[0580] AM=Adipose Midway Differentiated

[0581] U=Undifferentiated Stem Cells

[0582] Panel CNSD.01

[0583] The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0584] Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supemuclear Palsy, Depression, and “Normal controls”. Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

[0585] In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

[0586] PSP=Progressive supranuclear palsy

[0587] Sub Nigra=Substantia nigra

[0588] Glob Palladus=Globus palladus

[0589] Temp Pole=Temporal pole

[0590] Cing Gyr=Cingulate gyrus

[0591] BA 4 =Brodman Area 4

[0592] Panel CNS_Neurodegeneration_V1.0

[0593] The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0594] Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from “Normal controls” who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a “control” region within AD patients. Not all brain regions are represented in all cases.

[0595] In the labels employed to identify tissues in the CNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:

[0596] AD=Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

[0597] Control=Control brains; patient not demented, showing no neuropathology

[0598] Control (Path)=Control brains; patient not demented but showing sever AD-like

[0599] pathology

[0600] SupTemporal Ctx=Superior Temporal Cortex

[0601] Inf Temporal Ctx=Inferior Temporal Cortex

[0602] GPCR1a and GPCR1b

[0603] Expression of these GPCR1 genes (also referred to as SC35113271_A_da1, CG55798-03) was assessed using the primer-probe sets Ag1533 and Ag2269, described in Tables 16 and 17. Results of the RTQ-PCR runs are shown in Tables 18, 19, 20, 21, 22, 23 and 24. TABLE 16 Probe Name Ag1533 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-accatcatcaagagtgctatgg-3′ 22 431 119 Probe TET-5′-tcctttcgaagcttctgcatcatcct-3′-TAMRA 26 458 120 Reverse 5′-aggcatgtcagcaagaatacat-3′ 22 489 121

[0604] TABLE 17 Probe Name Ag2269 Start SEQ ID Primers Sequences Length Positon NO: Forward 5′-atggcatttgatcgctatgtag-3′ 22 365 122 Probe TET-5′-tgagatataccaccatcttgactccca-3′-TAMRA 27 402 123 Reverse 5′-ccatagcactcttgatgatggt-3′ 22 431 124

[0605] TABLE 18 CNS_neurodegeneration_v1.0 Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 225432469 Tissue Name 225432469 AD 1 Hippo 36.6 Control (Path) 3 16.5 Temporal Ctx AD 2 Hippo 11.6 Control (Path) 4 42.9 Temporal Ctx AD 3 Hippo 50.7 AD 1 Occipital Ctx 39.2 AD 4 Hippo 75.3 AD 2 Occipital Ctx 0.0 (Missing) AD 5 Hippo 20.4 AD 3 Occipital Ctx 25.9 AD 6 Hippo 69.3 AD 4 Occipital Ctx 82.9 Control 2 Hippo 22.5 AD 5 Occipital Ctx 11.0 Control 4 Hippo 53.2 AD 5 Occipital Ctx 7.1 Control (Path) 3 29.7 Control 1 Occipital 11.9 Hippo Ctx AD 1 Temporal Ctx 96.6 Control 2 Occipital 29.1 Ctx AD 2 Temporal Ctx 34.6 Control 3 Occipital 41.2 Ctx AD 3 Temporal Ctx 54.3 Control 4 Occipital 11.9 Ctx AD 4 Temporal Ctx 68.3 Control (Path) 1 23.3 Occipital Ctx AD 5 Inf Temporal 90.8 Control (Path) 2 14.3 Ctx Occipital Ctx AD 5 Sup Temporal 53.2 Control (Path) 3 35.1 Ctx Occipital Ctx AD 6 Inf Temporal 62.0 Control (Path) 4 30.8 Ctx Occipital Ctx AD 6 Sup Temporal 55.5 Control 1 Parietal 18.2 Ctx Ctx Control 1 Temporal 5.3 Control 2 Parietal 69.3 Ctx Ctx Control 2 Temporal 19.6 Control 3 Parietal 6.3 Ctx Ctx Control 3 Temporal 38.7 Control (Path) 1 33.9 Ctx Parietal Ctx Control 3 Temporal 17.0 Control (Path) 2 18.4 Ctx Parietal Ctx Control (Path) 1 29.1 Control (Path) 3 26.8 Temporal Ctx Parietal Ctx Control (Path) 2 23.7 Control (Path) 4 100.0 Temporal Ctx Parietal Ctx

[0606] TABLE 19 General_screening_panel_v1.4 Rel. Rel. Exp. (%) Exp. (%) Ag2269, Ag2269, Run Run Tissue Name 216861070 Tissue Name 216861070 Adipose 4.2 Renal ca. TK-10 0.7 Melanoma* 0.3 Bladder 16.0 Hs688(A).T Melanoma* 1.2 Gastric ca. (liver 8.7 Hs688(B).T met.) NCI-N87 Melanoma* M14 0.1 Gastric ca. KATO 0.0 III Melanoma* 0.0 Colon ca. SW-948 0.3 LOXIMVI Melanoma* SK 0.2 Colon ca. SW480 0.0 MEL-5 Squamous cell 100.0 Colon ca.* (SW480 0.1 carcinoma SCC-4 met) SW620 Testis Pool 3.2 Colon ca. HT29 0.0 Prostate ca.* 1.3 Colon ca. HCT-116 0.7 (bone met) PC-3 Prostate Pool 8.1 Colon ca. CaCo-2 0.2 Placenta 1.4 Colon cancer 0.5 tissue Uterus Pool 1.6 Colon ca. SW1116 0.1 Ovarian ca. 10.4 Colon ca. Colo-205 0.0 OVCAR-3 Ovarian ca. SK- 38.2 Colon ca. SW-48 0.0 OV-3 Ovarian ca. 0.0 Colon Pool 6.5 OVCAR-4 Ovarian ca. 1.3 Small Intestine 17.7 OVCAR-5 Pool Ovarian ca. 0.1 Stomach Pool 11.0 IGROV-1 Ovarian ca. 0.1 Bone Marrow Pool 3.5 OVCAR-8 Ovary 4.6 Fetal Heart 6.5 Breast ca. MCF-7 0.1 Heart Pool 4.1 Breast ca. MDA- 0.1 Lymph Node Pool 13.6 MB-231 Breast ca. BT 549 7.7 Fetal Skeletal 3.3 Muscle Breast ca. T47D 9.1 Skeletal Muscle 0.5 Pool Breast ca. MDA-N 8.4 Spleen Pool 8.9 Breast Pool 17.4 Thymus Pool 8.2 Trachea 9.0 CNS cancer (glio/ 0.3 astro) U87-MG Lung 5.1 CNS cancer (glio/ 1.0 astro) U-118-MG Fetal Lung 25.3 CNS cancer 0.0 (neuro;met) SK-N- AS Lung ca. NCI-N417 0.0 CNS cancer (astro) 0.7 SF-539 Lung ca. LX-1 0.0 CNS cancer (astro) 2.1 SNB-75 Lung ca. NCI-H146 0.7 CNS cancer (glio) 0.1 SNB-19 Lung ca. SHP-77 0.0 CNS cancer (glio) 6.8 SF-295 Lung ca. A549 0.4 Brain (Amygdala) 0.7 Pool Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.1 Lung ca. NCI-H23 1.6 Brain (fetal) 2.1 Lung ca. NCI-H460 51.8 Brain (Hippo- 1.1 campus) Pool Lung ca. HOP-62 3.4 Cerebral Cortex 0.4 Pool Lung ca. NCI-H522 0.1 Brain (Substantia 0.2 nigra) Pool Liver 0.2 Brain (Thalamus) 0.9 Pool Fetal Liver 2.6 Brain (whole) 0.7 Liver ca. HepG2 0.0 Spinal Cord Pool 8.4 Kidney Pool 20.0 Adrenal Gland 3.9 Fetal Kidney 25.0 Pituitary gland 0.2 Pool Renal ca. 786-0 0.3 Salivary Gland 0.4 Renal ca. A498 1.1 Thyroid (female) 0.5 Renal ca. ACHN 0.9 Pancreatic ca. 0.4 CAPAN2 Renal ca. UO-31 1.1 Pancreas Pool 10.2

[0607] TABLE 20 General_screening_panel_v1.5 Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Ag1533, Run Ag2269, Run Ag1533, Run Ag2269, Run Tissue Name 228632846 229393891 Tissue Name 228632846 229393891 Adipose 12.9 7.7 Renal ca. TK-10 2.4 1.2 Melanoma* 1.5 1.7 Bladder 43.8 24.7 Hs688(A).T Melanoma* 0.4 2.8 Gastric ca. (liver 54.7 46.3 Hs688(B).T met.) NCI-N87 Melanoma* 0.0 0.0 Gastric ca. 0.4 1.1 M14 KATO III Melanoma* 0.5 0.8 Colon ca. SW- 0.0 0.0 LOXIMVI 948 Melanoma* 0.3 1.2 Colon ca. SW480 0.0 0.0 SK-MEL-5 Squamous cell 0.0 1.3 Colon ca.* 0.0 0.0 carcinoma (SW480 met) SCC-4 SW620 Testis Pool 15.1 17.6 Colon ca. HT29 0.0 1.0 Prostate ca.* 1.9 2.0 Colon ca. HCT- 2.8 2.4 (bone met) 116 PC-3 Prostate Pool 23.7 17.9 Colon ca. CaCo-2 0.7 1.3 Placenta 2.9 5.1 Colon cancer 1.5 4.5 tissue Uterus Pool 11.5 15.5 Colon ca. 0.3 0.0 SW1116 Ovarian ca. 25.5 20.2 Colon ca. Colo- 0.0 0.5 OVCAR-3 205 Ovarian ca. 87.7 91.4 Colon ca. SW-48 0.0 0.0 SK-OV-3 Ovarian ca. 0.0 0.0 Colon Pool 37.4 28.7 OVCAR-4 Ovarian ca. 10.1 3.9 Small Intestine 43.5 33.4 OVCAR-5 Pool Ovarian ca. 0.0 0.7 Stomach Pool 27.4 21.3 IGROV-1 Ovarian ca. 2.4 1.4 Bone Marrow 22.1 20.6 OVCAR-8 Pool Ovary 22.2 27.2 Fetal Heart 57.0 36.9 Breast ca. 0.0 0.5 Heart Pool 12.2 9.2 MCF-7 Breast ca. 1.3 0.4 Lymph Node 66.9 47.6 MDA-MB- Pool 231 Breast ca. BT 1.4 3.3 Fetal Skeletal 11.4 10.5 549 Muscle Breast ca. 0.8 0.0 Skeletal Muscle 7.5 4.1 T47D Pool Breast ca. 0.7 0.4 Spleen Pool 21.3 13.2 MDA-N Breast Pool 59.5 62.0 Thymus Pool 38.7 31.9 Trachea 19.1 12.4 CNS cancer 1.6 4.0 (glio/astro) U87- MG Lung 27.2 17.1 CNS cancer 1.5 2.4 (glio/astro) U- 118-MG Fetal Lung 100.0 75.8 CNS cancer 0.0 0.0 (neuro;met) SK- N-AS Lung ca. NCI- 0.0 0.0 CNS cancer 1.1 0.5 N417 (astro) SF-539 Lung ca. LX- 0.4 0.0 CNS cancer 4.5 5.7 1 (astro) SNB-75 Lung ca. NCI- 4.7 3.7 CNS cancer 1.1 0.0 H146 (glio) SNB-19 Lung ca. 0.0 0.0 CNS cancer 20.6 29.1 SHP-77 (glio) SF-295 Lung ca. 2.9 1.0 Brain 2.1 1.3 A549 (Amygdala) Pool Lung ca. NCI- 0.0 0.0 Brain 0.9 0.6 H526 (cerebellum) Lung ca. NCI- 6.7 10.3 Brain (fetal) 7.9 7.3 H23 Lung ca. NCI- 9.2 1.9 Brain 1.6 2.6 H460 (Hippocampus) Pool Lung ca. 8.4 3.3 Cerebral Cortex 2.6 2.5 HOP-62 Pool Lung ca. NCI- 0.0 0.3 Brain (Substantia 2.0 0.8 H522 nigra) Pool Liver 0.4 0.2 Brain (Thalamus) 2.5 5.1 Pool Fetal Liver 8.7 6.5 Brain (whole) 3.8 2.6 Liver ca. 0.7 0.0 Spinal Cord Pool 5.0 3.6 HepG2 Kidney Pool 67.8 72.2 Adrenal Gland 11.0 11.3 Fetal Kidney 94.6 100.0 Pituitary gland 5.3 4.0 Pool Renal ca. 786- 1.2 4.2 Salivary Gland 1.7 1.4 0 Renal ca. 1.8 5.7 Thyroid (female) 2.5 5.5 A498 Renal ca. 3.6 2.8 Pancreatic ca. 4.7 6.3 ACHN CAPAN2 Renal ca. UO- 5.8 3.1 Pancreas Pool 39.8 24.1 31

[0608] TABLE 21 Panel 1.2 Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 142223910 Tissue Name 142223910 Endothelial cells 4.4 Renal ca. 786-0 1.8 Heart (Fetal) 3.9 Renal ca. A498 7.5 Pancreas 4.8 Renal ca. RXF 393 1.8 Pancreatic ca. 1.1 Renal ca. ACHN 5.0 CAPAN 2 Adrenal Gland 20.9 Renal ca. UO-31 9.0 Thyroid 1.1 Renal ca. TK-10 2.3 Salivary gland 52.1 Liver 9.8 Pituitary gland 0.7 Liver (fetal) 6.0 Brain (fetal) 0.7 Liver ca. 1.0 (hepatoblast) HepG2 Brain (whole) 0.0 Lung 1.5 Brain (amygdala) 1.0 Lung (fetal) 2.9 Brain (cere- 0.3 Lung ca. (small 0.2 bellum) cell) LX-1 Brain (hippo- 6.3 Lung ca. (small 5.2 campus) cell) NCI-H69 Brain (thalamus) 1.9 Lung ca. (s. cell 0.0 var.) SHP-77 Cerebral Cortex 9.2 Lung ca. (large 2.8 cell)NCI-H460 Spinal cord 2.9 Lung ca. (non-sm. 5.1 cell) A549 glio/astro U87-MG 1.6 Lung ca. (non- 10.2 s. cell) NCI-H23 glio/astro U- 1.1 Lung ca. (non- 28.3 118-MG s. cell) HOP-62 astrocytoma 1.2 Lung ca. (non- 2.0 SW1783 s. cl) NCI-H522 neuro*; met SK- 0.2 Lung ca. (squam.) 3.6 N-AS SW 900 astrocytoma SF- 7.4 Lung ca. (squam.) 0.7 539 NCI-H596 astrocytoma SNB- 1.6 Mammary gland 3.4 75 glioma SNB-19 8.1 Breast ca.* 1.3 (pl. ef) MCF-7 glioma U251 5.9 Breast ca.* 0.3 (pl. ef) MDA-MB-231 glioma SF-295 12.2 Breast ca.* 12.8 (pl. ef) T47D Heart 15.3 Breast ca. BT-549 2.9 Skeletal Muscle 4.9 Breast ca. MDA-N 0.8 Bone marrow 4.4 Ovary 9.3 Thymus 0.8 Ovarian ca. OVCAR-3 42.0 Spleen 5.6 Ovarian ca. OVCAR-4 1.4 Lymph node 1.6 Ovarian ca. OVCAR-5 18.2 Colorectal 10.9 Ovarian ca. OVCAR-8 0.0 Stomach 3.2 Ovarian ca. IGROV-1 0.0 Small intestine 7.8 Ovarian ca. 100.0 (ascites) SK-OV-3 Colon ca. SW480 0.0 Uterus 6.5 Colon ca.* SW620 0.0 Placenta 1.8 (SW480 met) Colon ca. HT29 0.9 Prostate 23.7 Colon ca. HCT-116 1.8 Prostate ca.* 4.5 (bone met) PC-3 Colon ca. CaCo-2 1.5 Testis 2.7 CC Well to Mod 2.9 Melanoma 0.2 Diff (ODO3866) Hs688(A).T Colon ca. HCC- 11.6 Melanoma* (met) 0.9 2998 Hs688(B).T Gastric ca. 44.4 Melanoma UACC-62 4.5 (liver met) NCI- N87 Bladder 98.6 Melanoma M14 4.2 Trachea 1.5 Melanoma LOX 0.4 IMVI Kidney 40.1 Melanoma* (met) 0.0 SK-MEL-5 Kidney (fetal) 25.5

[0609] TABLE 22 Panel 2D Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 145165498 Tissue Name 145165498 Normal Colon 48.0 Kidney Margin 6.1 8120608 CC Well to Mod 5.6 Kidney Cancer 0.0 Diff (ODO3866) 8120613 CC Margin 4.6 Kidney Margin 6.9 (ODO3866) 8120614 CC Gr.2 recto- 3.5 Kidney Cancer 10.2 sigmoid (ODO3868) 9010320 CC Margin 1.0 Kidney Margin 15.7 (ODO3868) 9010321 CC Mod Diff 4.4 Normal Uterus 36.3 (ODO3920) CC Margin 6.6 Uterine Cancer 45.7 (ODO3920) 064011 CC Gr.2 ascend 1.6 Normal Thyroid 8.1 colon (ODO3921) CC Margin 6.1 Thyroid Cancer 7.7 (ODO3921) CC from Partial 0.0 Thyroid Cancer 27.0 Hepatectomy A302152 (ODO4309) Mets Liver Margin 4.8 Thyroid Margin 29.5 (ODO4309) A302153 Colon mets to 4.3 Normal Breast 40.9 lung (OD04451-01) Lung Margin 1.2 Breast Cancer 3.5 (OD04451-02) Normal Prostate 26.1 Breast Cancer 18.9 6546-1 (OD04590-01) Prostate Cancer 64.2 Breast Cancer 34.6 (OD04410) Mets (OD04590-03) Prostate Margin 43.8 Breast Cancer 19.3 (OD04410) Metastasis Prostate Cancer 42.0 Breast Cancer 21.2 (OD04720-01) Prostate Margin 34.2 Breast Cancer 35.1 (OD04720-02) Normal Lung 31.9 Breast Cancer 7.7 9100266 Lung Met to Muscle 0.0 Breast Margin 2.9 (ODO4286) 9100265 Muscle Margin 1.9 Breast Cancer 14.8 (ODO4286) A209073 Lung Malignant 13.1 Breast Margin 23.3 Cancer (OD03126) A2090734 Lung Margin 26.8 Normal Liver 21.9 (OD03126) Lung Cancer 5.4 Liver Cancer 22.4 (OD04404) Lung Margin 37.9 Liver Cancer 1025 0.0 (OD04404) Lung Cancer 2.9 Liver Cancer 1026 2.1 (OD04565) Lung Margin 9.3 Liver Cancer 13.5 (OD04565) 6004-T Lung Cancer 24.8 Liver Tissue 5.9 (OD04237-01) 6004-N Lung Margin 10.5 Liver Cancer 0.0 (OD04237-02) 6005-T Ocular Mel Met 10.1 Liver Tissue 0.0 to Liver 6005-N (ODO4310) Liver Margin 8.7 Normal Bladder 42.0 (ODO4310) Melanoma 0.0 Bladder Cancer 5.8 Metastasis Lung Margin 25.0 Bladder Cancer 65.1 (OD04321) Normal Kidney 100.0 Bladder Cancer 5.6 (OD04718-01) Kidney Ca, 52.1 Bladder Normal 32.8 Nuclear grade Adjacent 2 (OD04338) (OD04718-03) Kidney Margin 22.1 Normal Ovary 5.7 (OD04338) Kidney Ca 41.5 Ovarian Cancer 9.4 Nuclear grade 1/2 (OD04339) Kidney Margin 46.0 Ovarian Cancer 8.8 (OD04339) (OD04768-07) Kidney Ca, Clear 27.0 Ovary Margin 3.3 cell (OD04768-08) type (OD04340) Kidney Margin 24.7 Normal Stomach 30.6 (OD04340) Kidney Ca, 9.1 Gastric Cancer 0.0 Nuclear grade 9060358 3 (OD04348) Kidney Margin 92.7 Stomach Margin 0.0 (OD04348) 9060359 Kidney Cancer 5.0 Gastric Cancer 5.3 (OD04622-01) 9060395 Kidney Margin 2.0 Stomach Margin 3.1 (OD04622-03) 9060394 Kidney Cancer 10.9 Gastric Cancer 4.7 (OD04450-01) 9060397 Kidney Margin 17.6 Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 0.8 Gastric Cancer 11.3 8120607 064005

[0610] TABLE 23 Panel 4.1D Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 223794696 Tissue Name 223794696 Secondary Th1 0.0 HUVEC IL-1beta 11.8 act Secondary Th2 20.4 HUVEC IFN gamma 11.5 act Secondary Tr1 13.1 HUVEC TNF 4.0 act alpha + IFN gamma Secondary Th1 25.3 HUVEC TNF 18.7 rest alpha + IL4 Secondary Th2 8.0 HUVEC IL-11 29.1 rest Secondary Tr1 33.9 Lung Micro- 83.5 rest vascular EC none Primary Th1 act 0.0 Lung Micro- 14.0 vascular EC TNFalpha + IL-1beta Primary Th2 act 25.0 Microvascular 8.5 Dermal EC none Primary Tr1 act 7.9 Microsvasular 0.0 Dermal EC TNFalpha + IL-1beta Primary Th1 rest 14.5 Bronchial 15.2 epithelium TNFalpha + IL1beta Primary Th2 rest 4.3 Small airway 0.0 epithelium none Primary Tr1 rest 20.7 Small airway 20.9 epithelium TNFalpha + IL-1beta CD45RA CD4 21.2 Coronery artery 0.0 lymphocyte act SMC rest CD45RO CD4 65.5 Coronery artery 0.0 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 25.9 Astrocytes rest 20.3 act Secondary CD8 19.6 Astrocytes 10.3 lymphocyte rest TNFalpha + IL-1beta Secondary CD8 4.5 KU-812 (Baso- 10.9 lymphocyte act phil) rest CD4 lymphocyte 53.2 KU-812 (Baso- 34.2 none phil) PMA/ionomycin 2ry Th1/Th2/ 19.2 CCD1106 0.0 Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 22.1 CCD1106 8.5 (Keratinocytes) TNFalpha + IL-1beta LAK cells IL-2 51.1 Liver cirrhosis 26.6 LAK cells 3.1 NCI-H292 none 19.9 IL-2 + IL-12 LAK cells 24.0 NCI-H292 IL-4 27.5 IL-2 + IFN gamma LAK cells 14.6 NCI-H292 IL-9 29.3 IL-2 + IL-18 LAK cells 0.0 NCI-H292 IL-13 16.2 PMA/ionomycin NK Cells IL-2 38.7 NCI-H292 IFN 44.1 rest gamma Two Way MLR 3 61.6 HPAEC none 8.5 day Two Way MLR 5 35.6 HPAEC TNF 10.7 day alpha + IL-1 beta Two Way MLR 7 9.9 Lung fibroblast 60.7 day none PBMC rest 26.2 Lung fibroblast 40.6 TNF alpha + IL-1 beta PBMC PWM 3.6 Lung fibroblast 8.8 IL-4 PBMC PHA-L 4.5 Lung fibroblast 21.3 IL-9 Ramos (B cell) 0.0 Lung fibroblast 4.8 none IL-13 Ramos (B cell) 0.0 Lung fibroblast 4.6 ionomycin IFN gamma B lymphocytes 5.1 Dermal fibro- 0.0 PWM blast CCD1070 rest B lymphocytes 17.0 Dermal fibro- 20.0 CD40L and IL-4 blast CCD1070 TNF alpha EOL-1 dbcAMP 10.9 Dermal fibro- 4.0 blast CCD1070 IL-1 beta EOL-1 dbcAMP 0.0 Dermal fibro- 10.7 PMA/ionomycin blast IFN gamma Dendritic cells 4.1 Dermal fibro- 26.6 none blast IL-4 Dendritic cells 17.7 Dermal Fibro- 10.4 LPS blasts rest Dendritic cells 14.8 Neutrophils 10.0 anti-CD40 TNFa + LPS Monocytes rest 10.7 Neutrophils 21.3 rest Monocytes LPS 16.4 Colon 0.0 Macrophages rest 18.6 Lung 4.2 Macrophages LPS 8.0 Thymus 100.0 HUVEC none 5.4 Kidney 81.8 HUVEC starved 2.6

[0611] TABLE 24 Panel 4D Rel. Rel. Exp. (%) Exp. (%) Ag2269, Ag2269, Run Run Tissue Name 151751515 Tissue Name 151751515 Secondary Th1 act 5.0 HUVEC IL-1beta 1.2 Secondary Th2 act 6.5 HUVEC IFN gamma 10.2 Secondary Tr1 act 2.3 HUVEC TNF alpha + IFN 1.9 gamma Secondary Th1 rest 3.5 HUVEC TNF alpha + IL4 1.2 Secondary Th2 rest 12.1 HUVEC IL-11 9.7 Secondary Tr1 rest 12.3 Lung Microvascular EC 17.7 none Primary Th1 act 3.8 Lung Microvascular EC 9.9 TNFalpha + IL-1beta Primary Th2 act 6.7 Microvascular Dermal EC 1.3 none Primary Tr1 act 4.9 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 56.6 Bronchial epithelium 0.0 TNFalpha + IL1beta Primary Th2 rest 11.0 Small airway epithelium 1.2 none Primary Tr1 rest 8.9 Small airway epithelium 27.5 TNFalpha + IL-1beta CD45RA CD4 5.3 Coronery artery SMC rest 3.9 lymphocyte act CD45RO CD4 21.8 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 5.3 Astrocytes rest 3.3 Secondary CD8 7.6 Astrocytes TNFalpha + 5.4 lymphocyte rest IL-1beta Secondary CD8 0.8 KU-812 (Basophil) rest 14.1 lymphocyte act CD4 lymphocyte none 22.5 KU-812 (Basophil) 25.7 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 4.8 CCD1106 (Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 25.3 CCD1106 (Keratinocytes) 1.3 TNFalpha + IL-1beta LAK cells IL-2 17.9 Liver cirrhosis 10.6 LAK cells IL-2 + IL-12 9.9 Lupus kidney 11.0 LAK cells IL-2 + IFN 40.9 NCI-H292 none 18.3 gamma LAK cells IL-2 + IL-18 21.2 NCI-H292 IL-4 28.1 LAK cells 4.0 NCI-H292 IL-9 32.3 PMA/ionomycin NK Cells IL-2 rest 15.8 NCI-H292 IL-13 12.4 Two Way MLR 3 day 35.6 NCI-H292 IFN gamma 23.3 Two Way MLR 5 day 3.6 HPAEC none 6.0 Two Way MLR 7 day 5.5 HPAEC TNF alpha + IL-1 1.5 beta PBMC rest 7.1 Lung fibroblast none 15.9 PBMC PWM 13.1 Lung fibroblast TNF alpha + 4.9 IL-1 beta PBMC PHA-L 1.6 Lung fibroblast IL-4 17.0 Ramos (B cell) none 2.8 Lung fibroblast IL-9 7.3 Ramos (B cell) 2.8 Lung fibroblast IL-13 15.9 ionomycin B lymphocytes PWM 7.9 Lung fibroblast IFN 10.0 gamma B lymphocytes CD40L 7.1 Dermal fibroblast 2.6 and IL-4 CCD1070 rest EOL-1 dbcAMP 5.1 Dermal fibroblast 6.0 CCD1070 TNF alpha EOL-1 dbcAMP 1.4 Dermal fibroblast 2.6 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 1.9 Dermal fibroblast IFN 3.5 gamma Dendritic cells LPS 9.1 Dermal fibroblast IL-4 6.7 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 5.5 IBD Crohn's 0.0 Monocytes LPS 5.3 Colon 33.2 Macrophages rest 1.7 Lung 19.1 Macrophages LPS 1.2 Thymus 52.1 HUVEC none 10.1 Kidney 100.0 HUVEC starved 5.0

[0612] CNS_neurodegeneration_v1.0 Summary: Ag1533 The GPCR1a and GPCR1b genes show widespread expression across all regions of the brain, with highest expression in the parietal cortex of a control patient (CT=33.5). The GPCR1a and GPCR1 genes appear to be upregulated in the temporal cortex of patients with Alzheimer's disease. The temporal cortex is a region which shows severe degeneration in Alzheimer's disease, suggesting the expression of these genes may play a role in the pathogenesis of this disease. Therapeutic modulation of the GPCR1a and GPCR1b genes or treatment with an antagonist to the receptor may be of benefit in treating Alzheimer's disease or dementia.

[0613] General_screening_panel_v1.4 Summary: Ag2269 Highest expression of the GPCR1 a and GPCR1b genes is detected in the squamous cell carcinoma cell line SCC4 (CT=28.3). Significant expression is also seen in cell lines derived from lung and ovarian cancer. Thus, expression of these genes could be used to differentiate between these cell lines and other samples in this panel. Furthermore, therapeutic modulation of the expression or function of the protein encoded by the GPCR1 a and GPCR1b genes could be useful in the treatment of lung, ovarian or squamous cell carcinoma.

[0614] Among tissues with metabolic function, the GPCR1a and GPCR1b genes are moderately expressed (CT values=32-33) in adipose, adult and fetal heart, fetal skeletal muscle, adrenal and pancreas. Thus, these gene products may be a small molecule drug target z z for the treatment of metabolic disease, including obesity and Types 1 and 2 diabetes.

[0615] The GPCR1a and GPCR1b genes are expressed at low levels in the fetal brain and moderate levels in the spinal cord. The encoded proteins are homologous to the GPCR family of receptors. Several neurotransmitter receptors are GPCRs, including the dopamine receptor family, the serotonin receptor family, the GABAB receptor, muscarinic acetylcholine receptors, and others; thus this GPCR may represent a novel neurotransmitter receptor. Targeting various neurotransmitter receptors (dopamine, serotonin) has proven to be an effective therapy in psychiatric illnesses such as schizophrenia, bipolar disorder and depression. Therapeutic modulation of these genes or their protein products may be beneficial in one or more of these diseases, as may blockade of the receptor coded for by these genes. Levels of the GPCR1a and GPCR1b genes are considerably higher, however, in areas outside of the central nervous system (such as kidney and fetal lung), suggesting the possibility of a wider role in intercellular signaling.

[0616] General_screening_panel_v1.5 Summary: Ag1533/Ag2269 Two runs with two different probes and primers show highest expression in the fetal lung and kidney (CTs=30). Significant levels of expression are also detected in adult kidney and lung. This expression profile suggests that the GPCR1a and GPCR1b gene products may be involved in the normal homeostasis of these organs. Therefore, therapeutic modulation of the expression or function of these genes may be effective in the treatment of diseases of these organs including diabetes, polycystic kidney disease, systemic lupus erythematosus, asthma, emphysema, and acute respiratory distress syndrome (ARDS).

[0617] The GPCR1a and GPCR1b genes are also moderately expressed in a a variety of metabolic tissues including adipose, adult and fetal heart, adult and fetal skeletal muscle, adrenal, pituitary, thyroid and pancreas. Thus, these gene products may be a small molecule drug target for the treatment of metabolic disease, including obesity and Types 1 and 2 diabetes. Furthermore, this gene is differentially expressed in adult (CT value=38) versus fetal liver (CT values=33-34), and may be used to differentiate between the adult and fetal phenotype in this tissue.

[0618] There is moderate expression in some tissues of the central nervous system, including the fetal brain and the spinal cord. Please see Panel General_screening_panel_v1.4 Summary for discussion of potential utility in the central nervous system.

[0619] There is also significant expression of the GPCR1a and GPCR1b genes in a cell lines derived from ovarian cancer and gastric cancer. Please see Panel 1.2 for discussion of utility of this gene in the context of this expression profile.

[0620] Panel 1.2 Summary: Ag1533 The expression of the GPCR1a and GPCR1b genes is highest in a sample derived from an ovarian cancer cell line (CT=29.1). Interestingly, this cell line was derived from a unique form of ovarian cancer, ascites. In addition, there appears to be substantial expression of this gene in samples derived from other ovarian cancer cell lines as well as normal bladder tissue, normal kidney tissue and a cell lined derived from a gastric cancer. Thus, the expression of these genes in these tissues could be used to distinguish these samples from other samples in the panel. Additionally, the expression of the GPCR1a and GPCR1b genes could be used to distingush ascites derived samples from other samples in the panel. Furthermore, therapeutic modulation of this gene, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of ovarian cancer.

[0621] The GPCR1a and GPCR1b genes are also expressed at moderate levels in a variety of metabolic tissues including adult and fetal liver, adult and fetal heart, skeletal muscle, adrenal and pancreas. This widespread expression suggests that the protein encoded by these genes could be useful in the treatment of metabolic diseases, including obesity and diabetes.

[0622] Panel 2D Summary: Ag1533 The expression of the GPCR1a and GPCR1b genes appears to be highest in a sample derived from normal kidney tissue (CT=31.9). In addition, there is substantial expression in samples derived from other samples of normal kidney tissue adjacent to malignant kidney. Moreover, there also appears to be expression associated with tissues, normal or malignant, derived from uterus, prostate, breast, bladder and thyroid. Thus, the expression of these genes could be used to distinguish samples derived from these tissue types when compared to other samples in the panel. Further, therapeutic modulation of these genes, or gene products, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of cancers of the above listed tissues.

[0623] Panel 4.1D Summary: Ag1533: These transcripts is expressed on most tissues in panel 4.1D regardless of treatment, with highest expression in the thymus (CT=32.8). These transcripts encodes a GPCR-like molecule with potential signaling activity and may important in maintaining normal cellular functions in a number of tissues. Therapies designed with the protein encoded for by these transcripts could be important in regulating cellular viability or function.

[0624] Panel 4D Summary: Ag2269 These transcripts are expressed on most tissues in panel 4D regardless of treatment, with highest expression in the kidney (CT31.3). These transcripts encode a GPCR-like molecule with potential signaling activity and may important in maintaining normal cellular functions in a number of tissues. Therapies designed with the proteins encoded for by these transcripts could be important in regulating cellular viability or function

[0625] GPCR1 c

[0626] Expression of the GPCR1c gene (also referred to as CG55798-04) was assessed using the primer-probe sets Ag1533, Ag2617 and Ag2862, described in Tables 25, 26 and 27. Results of the RTQ-PCR runs are shown in Tables 28, 29, 30, 31, 32, 33 and 34. TABLE 25 Probe Name Ag 1533 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-accatcatcaagagtgctatgg-3′ 22 431 125 Probe TET-5′-tcctttcgaagcttctgcatcatcct-3′-TAMRA 26 458 126 Reverse 5′-aggcatgtcagcaagaatacat-3′ 22 489 127

[0627] TABLE 26 Probe Name Ag2617 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-ccatggcatttgatcactatgt-3′ 22 363 128 Probe TET-5′-tgagatataccaccatcttgactccca-3′-TAMRA 27 402 129 Reverse 5′-ccatagcactcttgatgatggt-3′ 22 431 130

[0628] TABLE 27 Probe Name Ag2862 SEQ ID Primers Sequences Length Start Positon NO: Forward 5′-ccatggcatttgatcactatgt-3′ 22 363 131 Probe TET 5′-tgagatataccaccatcttgactccca-3′-TAMRA 27 402 129 Reverse 5′-ccatagcactcttgatgatggt-3′ 22 431 130

[0629] TABLE 28 CNS_neurodegeneration_v1.0 Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 225432469 Tissue Name 225432469 AD 1 Hippo 36.6 Control (Path) 3 16.5 Temporal Ctx AD 2 Hippo 11.6 Control (Path) 4 42.9 Temporal Ctx AD 3 Hippo 50.7 AD 1 Occipital Ctx 39.2 AD 4 Hippo 75.3 AD 2 Occipital Ctx 0.0 (Missing) AD 5 Hippo 20.4 AD 3 Occipital Ctx 25.9 AD 6 Hippo 69.3 AD 4 Occipital Ctx 82.9 Control 2 Hippo 22.5 AD 5 Occipital Ctx 11.0 Control 4 Hippo 53.2 AD 5 Occipital Ctx 7.1 Control (Path) 3 29.7 Control 1 Occipital 11.9 Hippo Ctx AD 1 Temporal Ctx 96.6 Control 2 Occipital 29.1 Ctx AD 2 Temporal Ctx 34.6 Control 3 Occipital 41.2 Ctx AD 3 Temporal Ctx 54.3 Control 4 Occipital 11.9 Ctx AD 4 Temporal Ctx 68.3 Control (Path) 1 23.3 Occipital Ctx AD 5 Inf Temporal 90.8 Control (Path) 2 14.3 Ctx Occipital Ctx AD 5 Sup Temporal 53.2 Control (Path) 3 35.1 Ctx Occipital Ctx AD 6 Inf Temporal 62.0 Control (Path) 4 30.8 Ctx Occipital Ctx AD 6 Sup Temporal 55.5 Control 1 Parietal 18.2 Ctx Ctx Control 1 Temporal 5.3 Control 2 Parietal 69.3 Ctx Ctx Control 2 Temporal 19.6 Control 3 Parietal 6.3 Ctx Ctx Control 3 Temporal 38.7 Control (Path) 1 33.9 Ctx Parietal Ctx Control 3 Temporal 17.0 Control (Path) 2 18.4 Ctx Parietal Ctx Control (Path) 1 29.1 Control (Path) 3 26.8 Temporal Ctx Parietal Ctx Control (Path) 2 23.7 Control (Path) 4 100.0 Temporal Ctx Parietal Ctx

[0630] TABLE 29 General_screening_panel_v1.5 Rel. Rel. Exp. (%) Exp. (%) Ag1533, Ag1533, Run Run Tissue Name 228632846 Tissue Name 228632846 Adipose 12.9 Renal ca. TK-10 2.4 Melanoma* 1.5 Bladder 43.8 Hs688(A).T Melanoma* 0.4 Gastric ca. (liver 54.7 Hs688(B).T met.) NCI-N87 Melanoma* M14 0.0 Gastric ca. KATO 0.4 III Melanoma* 0.5 Colon ca. SW-948 0.0 LOXIMVI Melanoma* SK- 0.3 Colon ca. SW480 0.0 MEL-5 Squamous cell 0.0 Colon ca.* (SW480 0.0 carcinoma SCC-4 met) SW620 Testis Pool 15.1 Colon ca. HT29 0.0 Prostate ca.* 1.9 Colon ca. HCT-116 2.8 (bone met) PC-3 Prostate Pool 23.7 Colon ca. CaCo-2 0.7 Placenta 2.9 Colon cancer tissue 1.5 Uterus Pool 11.5 Colon ca. SW1116 0.3 Ovarian ca. 25.5 Colon ca. Colo-205 0.0 OVCAR-3 Ovarian ca. SK- 87.7 Colon ca. SW-48 0.0 OV-3 Ovarian ca. 0.0 Colon Pool 37.4 OVCAR-4 Ovarian ca. 10.1 Small Intestine 43.5 OVCAR-5 Pool Ovarian ca. 0.0 Stomach Pool 27.4 IGROV-1 Ovarian ca. 2.4 Bone Marrow Pool 22.1 OVCAR-8 Ovary 22.2 Fetal Heart 57.0 Breast ca. MCF- 0.0 Heart Pool 12.2 7 Breast ca. MDA- 1.3 Lymph Node Pool 66.9 MB-231 Breast ca. BT 1.4 Fetal Skeletal 11.4 549 Muscle Breast ca. T47D 0.8 Skeletal Muscle 7.5 Pool Breast ca. MDA- 0.7 Spleen Pool 21.3 N Breast Pool 59.5 Thymus Pool 38.7 Trachea 19.1 CNS cancer (glio/ 1.6 astro) U87-MG Lung 27.2 CNS cancer (glio/ 1.5 astro) U-118-MG Fetal Lung 100.0 CNS cancer 0.0 (neuro;met) SK-N- AS Lung ca. NCI- 0.0 CNS cancer (astro) 1.1 N417 SF-539 Lung ca. LX-1 0.4 CNS cancer (astro) 4.5 SNB-75 Lung ca. NCI- 4.7 CNS cancer (glio) 1.1 H146 SNB-19 Lung ca. SHP-77 0.0 CNS cancer (glio) 20.6 SF-295 Lung ca. A549 2.9 Brain (Amygdala) 2.1 Pool Lung ca. NCI- 0.0 Brain (cerebellum) 0.9 H526 Lung ca. NCI- 6.7 Brain (fetal) 7.9 H23 Lung ca. NCI- 9.2 Brain (Hippocampus) 1.6 H460 Pool Lung ca. HOP-62 8.4 Cerebral Cortex 2.6 Pool Lung ca. NCI- 0.0 Brain (Substantia 2.0 H522 nigra) Pool Liver 0.4 Brain (Thalamus) 2.5 Pool Fetal Liver 8.7 Brain (whole) 3.8 Liver ca. HepG2 0.7 Spinal Cord Pool 5.0 Kidney Pool 67.8 Adrenal Gland 11.0 Fetal Kidney 94.6 Pituitary gland 5.3 Pool Renal ca. 786-0 1.2 Salivary Gland 1.7 Renal ca. A498 1.8 Thyroid (female) 2.5 Renal ca. ACHN 3.6 Pancreatic ca. 4.7 CAPAN2 Renal ca. UO-31 5.8 Pancreas Pool 39.8

[0631] TABLE 30 Panel 1.2 Rel. Exp. (%) Ag1533, Rel. Exp. (%) Ag1533, Tissue Name Run 142223910 Tissue Name Run 142223910 Endothelial cells 4.4 Renal ca. 786-0 1.8 Heart (Fetal) 3.9 Renal ca. A498 7.5 Pancreas 4.8 Renal ca. RXF 393 1.8 Pancreatic ca. 1.1 Renal ca. ACHN 5.0 CAPAN 2 Adrenal Gland 20.9 Renal ca. UO-31 9.0 Thyroid 1.1 Renal ca. TK-10 2.3 Salivary gland 52.1 Liver 9.8 Pituitary gland 0.7 Liver (fetal) 6.0 Brain (fetal) 0.7 Liver ca. 1.0 (hepatoblast) HepG2 Brain (whole) 0.0 Lung 1.5 Brain (amygdala) 1.0 Lung (fetal) 2.9 Brain (cerebellum) 0.3 Lung ca. (small cell) 0.2 LX-1 Brain (hippocampus) 6.3 Lung ca. (small cell) 5.2 NCI-H69 Brain (thalamus) 1.9 Lung ca. (s. cell var.) 0.0 SHP-77 Cerebral Cortex 9.2 Lung ca. (large 2.8 cell) NCI-H460 Spinal cord 2.9 Lung ca. (non-sm. 5.1 cell) A549 Glio/astro U87-MG 1.6 Lung ca. (non-s. cell) 10.2 NCI-H23 Glio/astro U-118-MG 1.1 Lung ca. (non-s. cell) 28.3 HOP-62 astrocytoma SW1783 1.2 Lung ca. (non-s.cl) 2.0 NCI-H522 Neuro*; met SK-N-AS 0.2 Lung ca. (squam.) 3.6 SW 900 astrocytoma SF-539 7.4 Lung ca. (squam.) 0.7 NCI-H596 astrocytoma SNB-75 1.6 Mammary gland 3.4 glioma SNB-19 8.1 Breast ca.* (pl. ef) 1.3 MCF-7 glioma U251 5.9 Breast ca.* (pl. ef) 0.3 MDA-MB-231 glioma SF-295 12.2 Breast ca.* (pl. ef) 12.8 T47D Heart 15.3 Breast ca. BT-549 2.9 Skeletal Muscle 4.9 Breast ca. MDA-N 0.8 Bone marrow 4.4 Ovary 9.3 Thymus 0.8 Ovarian ca. OVCAR-3 42.0 Spleen 5.6 Ovarian ca. OVCAR-4 1.4 Lymph node 1.6 Ovarian ca. OVCAR-5 18.2 Colorectal 10.9 Ovarian ca. OVCAR-8 0.0 Stomach 3.2 Ovarian ca. IGROV-1 0.0 Small intestine 7.8 Ovarian ca. (ascites) 100.0 SK-OV-3 Colon ca. SW480 0.0 Uterus 6.5 Colon ca.* SW620 0.0 Placenta 1.8 (SW480 met) Colon ca. HT29 0.9 Prostate 23.7 Colon ca. HCT-116 1.8 Prostate ca.* (bone 4.5 met) PC-3 Colon ca. CaCo-2 1.5 Testis 2.7 CC Well to Mod Diff 2.9 Melanoma 0.2 (ODO3866) Hs688 (A).T Colon ca. HCC-2998 11.6 Melanoma* (met) 0.9 Hs688 (B).T Gastric ca. (liver met) 44.4 Melanoma UACC-62 4.5 NCI-N87 Bladder 98.6 Melanoma M14 4.2 Trachea 1.5 Melanoma LOX 0.4 IMVI Kidney 40.1 Melanoma* (met) 0.0 SK-MEL-5 Kidney (fetal) 25.5

[0632] TABLE 31 Panel 1.3D Rel. Exp. (%) Ag2617, Rel. Exp. (%) Ag2617, Tissue Name Run 167644078 Tissue Name Run 167644078 Liver adenocarcinoma 2.3 Kidney (fetal) 15.0 Pancreas 2.2 Renal ca. 786-0 1.5 Pancreatic ca. 0.0 Renal ca. A498 3.1 CAPAN 2 Adrenal gland 0.0 Renal ca. RXF 393 0.0 Thyroid 1.5 Renal ca. ACHN 2.2 Salivary gland 3.2 Renal ca. UO-31 0.0 Pituitary gland 6.1 Renal ca. TK-10 2.4 Brain (fetal) 2.9 Liver 2.5 Brain (whole) 0.0 Liver (fetal) 0.0 Brain (amygdala) 0.0 Liver ca. 0.0 (hepatoblast) HepG2 Brain (cerebellum) 0.0 Lung 2.6 Brain (hippocampus) 3.2 Lung (fetal) 4.0 Brain (substantia nigra) 2.3 Lung ca. (small cell) 0.0 LX-1 Brain (thalamus) 0.0 Lung ca. (small cell) 0.0 NCI-H69 Cerebral Cortex 1.3 Lung ca. (s. cell var.) 0.0 SHP-77 Spinal cord 3.4 Lung ca. (large 0.0 cell) NCI-H460 glio/astro U87-MG 0.0 Lung ca. (non-sm. 0.0 cell) A549 glio/astro U-118-MG 1.5 Lung ca. (non-s. cell) 4.7 NCI-H23 astrocytoma SW1783 2.0 Lung ca. (non-s. cell) 2.1 HOP-62 Neuro*; met SK-N-AS 0.0 Lung ca. (non-s. cl) 0.0 NCI-H522 astrocytoma SF-539 6.3 Lung ca. (squam.) 3.0 SW 900 astrocytoma SNB-75 1.4 Lung ca. (squam.) 0.0 NCI-H596 glioma SNB-19 2.5 Mammary gland 3.3 glioma U251 16.6 Breast ca.* (pl. ef) 0.0 MCF-7 glioma SF-295 12.5 Breast ca.* (pl. ef) 0.0 MDA-MB-231 Heart (Fetal) 0.0 Breast ca.* (pl. ef) 1.4 T47D Heart 2.1 Breast ca. BT-549 1.3 Skeletal muscle (Fetal) 3.1 Breast ca. MDA-N 1.7 Skeletal muscle 0.0 Ovary 0.0 Bone marrow 1.9 Ovarian ca. OVCAR-3 9.2 Thymus 4.1 Ovarian ca. OVCAR-4 0.0 Spleen 1.6 Ovarian ca. OVCAR-5 9.2 Lymph node 7.1 Ovarian ca. OVCAR-8 5.1 Colorectal 3.8 Ovarian ca. IGROV-1 0.0 Stomach 0.0 Ovarian ca. (ascites) 100.0 SK-OV-3 Small intestine 1.4 Uterus 5.1 Colon ca. SW480 1.5 Placenta 0.0 Colon ca.* SW620 0.0 Prostate 4.5 (SW480 met) Colon ca. HT29 1.0 Prostate ca.* (bone 1.0 met) PC-3 Colon ca. HCT-116 0.0 Testis 5.4 Colon ca. CaCo-2 0.0 Melanoma 0.0 Hs688 (A).T CC Well to Mod Diff 0.0 Melanoma* (met) 0.9 (ODO3866) Hs688 (B).T Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca. (liver met) 12.7 Melanoma M14 0.0 NCI-N87 Bladder 16.4 Melanoma LOX 0.0 IMVI Trachea 4.1 Melanoma* (met) 0.0 SK-MEL-5 Kidney 0.0 Adipose 12.3

[0633] TABLE 32 Panel 2D Rel. Exp. (%) Ag1533, Rel. Exp. (%) Ag1533, Tissue Name Run 145165498 Tissue Name Run 145165498 Normal Colon 48.0 Kidney Margin 6.1 8120608 CC Well to Mod Diff 5.6 Kidney Cancer 0.0 (ODO3866) 8120613 CC Margin (ODO3866) 4.6 Kidney Margin 6.9 8120614 CC Gr.2 rectosigmoid 3.5 Kidney Cancer 10.2 (ODO3868) 9010320 CC Margin (ODO3868) 1.0 Kidney Margin 15.7 9010321 CC Mod Diff (ODO3920) 4.4 Normal Uterus 36.3 CC Margin (ODO3920) 6.6 Uterine Cancer 45.7 064011 CC Gr.2 ascend colon 1.6 Normal Thyroid 8.1 (ODO3921) CC Margin (ODO3921) 6.1 Thyroid Cancer 7.7 CC from Partial 0.0 Thyroid Cancer 27.0 Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 4.8 Thyroid Margin 29.5 A302153 Colon mets to lung 4.3 Normal Breast 40.9 (OD04451-01) Lung Margin (OD04451- 1.2 Breast Cancer 3.5 02) Normal Prostate 6546-1 26.1 Breast Cancer 18.9 (OD04590-01) Prostate Cancer 64.2 Breast Cancer Mets 34.6 (OD04410) (OD04590-03) Prostate Margin 43.8 Breast Cancer 19.3 (OD04410) Metastasis Prostate Cancer 42.0 Breast Cancer 21.2 (OD04720-01) Prostate Margin 34.2 Breast Cancer 35.1 (OD04720-02) Normal Lung 31.9 Breast Cancer 7.7 9100266 Lung Met to Muscle 0.0 Breast Margin 2.9 (ODO4286) 9100265 Muscle Margin 1.9 Breast Cancer 14.8 (ODO4286) A209073 Lung Malignant Cancer 13.1 Breast Margin 23.3 (OD03126) A2090734 Lung Margin (OD03126) 26.8 Normal Liver 21.9 Lung Cancer (OD04404) 5.4 Liver Cancer 22.4 Lung Margin (OD04404) 37.9 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 2.9 Liver Cancer 1026 2.1 Lung Margin (OD04565) 9.3 Liver Cancer 6004-T 13.5 Lung Cancer (OD04237- 24.8 Liver Cancer 6004-N 5.9 01) Lung Margin (OD04237- 10.5 Liver Cancer 6005-T 0.0 02) Ocular Mel Met to Liver 10.1 Liver Tissue 6005-N 0.0 (ODO4310) Liver Margin (ODO4310) 8.7 Normal Bladder 42.0 Melanoma Metastasis 0.0 Bladder Cancer 5.8 Lung Margin (OD04321) 25.0 Bladder Cancer 65.1 Normal Kidney 100.0 Bladder Cancer 5.6 (OD04718-01) Kidney Ca, Nuclear grade 52.1 Bladder Normal 32.8 2 (OD04338) Adjacent (OD04718-03) Kidney Margin 22.1 Normal Ovary 5.7 (OD04338) Kidney Ca Nuclear grade 41.5 Ovarian Cancer 9.4 1/2 (OD04339) Kidney Margin 46.0 Ovarian Cancer 8.8 (OD04339) (OD04768-07) Kidney Ca, Clear cell 27.0 Ovary Margin 3.3 type (OD04340) (OD04768-08) Kidney Margin 24.7 Normal Stomach 30.6 (OD04340) Kidney Ca, Nuclear grade 9.1 Gastric Cancer 0.0 3 (OD04348) 9060358 Kidney Margin 92.7 Stomach Margin 0.0 (OD04348) 9060359 Kidney Cancer 5.0 Gastric Cancer 5.3 (OD04622-01) 9060395 Kidney Margin 2.0 Stomach Margin 3.1 (OD04622-03) 9060394 Kidney Cancer 10.9 Gastric Cancer 4.7 (OD04450-01) 9060397 Kidney Margin 17.6 Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 8120607 0.8 Gastric Cancer 11.3 064005

[0634] TABLE 33 Panel 4.1D Rel. Exp. (%) Ag1533, Rel. Exp. (%) Ag1533, Tissue Name Run 223794696 Tissue Name Run 223794696 Secondary Th1 act 0.0 HUVEC IL-1beta 11.8 Secondary Th2 act 20.4 HUVEC IFN gamma 11.5 Secondary Tr1 act 13.1 HUVEC TNF alpha + IFN 4.0 gamma Secondary Th1 rest 25.3 HUVEC TNF alpha + IL4 18.7 Secondary Th2 rest 8.0 HUVEC IL-11 29.1 Secondary Tr1 rest 33.9 Lung Microvascular EC 83.5 none Primary Th1 act 0.0 Lung Microvascular EC 14.0 TNFalpha + IL-1beta Primary Th2 act 25.0 Microvascular Dermal EC 8.5 none Primary Tr1 act 7.9 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 14.5 Bronchial epithelium 15.2 TNFalpha + IL1beta Primary Th2 rest 4.3 Small airway epithelium 0.0 none Primary Tr1 rest 20.7 Small airway epithelium 20.9 TNFalpha + IL-1beta CD45RA CD4 21.2 Coronery artery SMC rest 0.0 lymphocyte act CD45RO CD4 65.5 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 25.9 Astrocytes rest 20.3 Secondary CD8 19.6 Astrocytes TNFalpha + 10.3 lymphocyte rest IL-1beta Secondary CD8 4.5 KU-812 (Basophil) rest 10.9 lymphocyte act CD4 lymphocyte none 53.2 KU-812 (Basophil) 34.2 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 19.2 CCD1106 (Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 22.1 CCD1106 (Keratinocytes) 8.5 TNFalpha + IL-1beta LAK cells IL-2 51.1 Liver cirrhosis 26.6 LAK cells IL-2 + IL-12 3.1 NCI-H292 none 19.9 LAK cells IL-2 + IFN 24.0 NCI-H292 IL-4 27.5 gamma LAK cells IL-2 + IL-18 14.6 NCI-H292 IL-9 29.3 LAK cells 0.0 NCI-H292 IL-13 16.2 PMA/ionomycin NK Cells IL-2 rest 38.7 NCI-H292 IFN gamma 44.1 Two Way MLR 3 day 61.6 HPAEC none 8.5 Two Way MLR 5 day 35.6 HPAEC TNF alpha + IL-1 10.7 beta Two Way MLR 7 day 9.9 Lung fibroblast none 60.7 PBMC rest 26.2 Lung fibroblast TNF alpha + 40.6 IL-1 beta PBMC PWM 3.6 Lung fibroblast IL-4 8.8 PBMC PHA-L 4.5 Lung fibroblast IL-9 21.3 Ramos (B cell) none 0.0 Lung fibroblast IL-13 4.8 Ramos (B cell) 0.0 Lung fibroblast IFN 4.6 ionomycin gamma B lymphocytes PWM 5.1 Dermal fibroblast 0.0 CCD1070 rest B lymphocytes CD40L 17.0 Dermal fibroblast 20.0 and IL-4 CCD1070 TNF alpha EOL-1 dbcAMP 10.9 Dermal fibroblast 4.0 CCD1070 IL-1 beta EOL-1 dbcAMP 0.0 Dermal fibroblast IFN 10.7 PMA/ionomycin gamma Dendritic cells none 4.1 Dermal fibroblast IL-4 26.6 Dendritic cells LPS 17.7 Dermal Fibroblasts rest 10.4 Dendritic cells anti- 14.8 Neutrophils TNFa + LPS 10.0 CD40 Monocytes rest 10.7 Neutrophils rest 21.3 Monocytes LPS 16.4 Colon 0.0 Macrophages rest 18.6 Lung 4.2 Macrophages LPS 8.0 Thymus 100.0 HUVEC none 5.4 Kidney 81.8 HUVEC starved 2.6

[0635] TABLE 34 Panel 4D Rel. Exp. (%) Ag2862, Rel. Exp. (%) Ag2862, Tissue Name Run 164299494 Tissue Name Run 164299494 Secondary Th1 act 0.0 HUVEC IL-1beta 0.0 Secondary Th2 act 10.9 HUVEC IFN gamma 4.2 Secondary Tr1 act 2.6 HUVEC TNF alpha + IFN 2.5 gamma Secondary Th1 rest 4.5 HUVEC TNF alpha + IL4 4.6 Secondary Th2 rest 13.8 HUVEC IL-11 2.4 Secondary Tr1 rest 9.8 Lung Microvascular EC 28.9 none Primary Th1 act 0.0 Lung Microvascular EC 13.2 TNFalpha + IL-1beta Primary Th2 act 0.0 Microvascular Dermal EC 11.7 none IPrimary Tr1 act 0.0 Microsvasular Dermal EC 4.3 TNFalpha + IL-1beta Primary Th1 rest 65.5 Bronchial epithelium 9.7 TNFalpha + IL1beta Primary Th2 rest 24.0 Small airway epithelium 1.7 none Primary Tr1 rest 6.8 Small airway epithelium 36.1 TNFalpha + IL-1beta CD45RA CD4 12.9 Coronery artery SMC rest 11.1 lymphocyte act CD45RO CD4 7.4 Coronery artery SMC 6.7 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 9.4 Secondary CD8 13.7 Astrocytes TNFalpha + 8.0 lymphocyte rest IL-1beta Secondary CD8 0.0 KU-812 (Basophil) rest 5.9 lymphocyte act CD4 lymphocyte none 22.1 KU-812 (Basophil) 25.9 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 20.2 CCD1106 (Keratinocytes) 6.5 CD95 CH11 none LAK cells rest 20.7 CCD1106 (Keratinocytes) 2.9 TNFalpha + IL-1beta LAK cells IL-2 53.2 Liver cirrhosis 17.8 LAK cells IL-2 + IL-12 27.4 Lupus kidney 13.9 LAK cells IL-2 + IFN 73.2 NCI-H292 none 23.2 gamma LAK cells IL-2 + IL-18 12.6 NCI-H292 IL-4 28.3 LAK cells 0.0 NCI-H292 IL-9 24.1 PMA/ionomycin NK Cells IL-2 rest 26.8 NCI-H292 IL-13 2.3 Two Way MLR 3 day 82.9 NCI-H292 IFN gamma 24.1 Two Way MLR 5 day 12.1 HPAEC none 8.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1 6.3 beta PBMC rest 8.9 Lung fibroblast none 9.9 PBMC PWM 17.4 Lung fibroblast TNF alpha + 18.8 IL-1 beta PBMC PHA-L 7.0 Lung fibroblast IL-4 11.7 Ramos (B cell) none 0.0 Lung fibroblast IL-9 18.7 Ramos (B cell) 4.5 Lung fibroblast IL-13 20.0 ionomycin B lymphocytes PWM 2.5 Lung fibroblast IFN 17.3 gamma B lymphocytes CD40L 12.9 Dermal fibroblast 3.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 4.7 Dermal fibroblast 9.9 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 5.1 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 1.8 Dermal fibroblast IFN 1.7 gamma Dendritic cells LPS 2.8 Dermal fibroblast IL-4 24.5 Dendritic cells anti- 0.0 IBD Colitis 2 1.8 CD40 Monocytes rest 6.0 IBD Crohn's 2.1 Monocytes LPS 0.0 Colon 14.9 Macrophages rest 0.0 Lung 11.7 Macrophages LPS 11.9 Thymus 82.9 HUVEC none 0.0 Kidney 100.0 HUVEC starved 3.1

[0636] CNS_neurodegeneration_v1.0 Summary: Ag1533 The GPCR1c gene shows widespread expression across all regions of the brain, with highest expression in the parietal cortex of a control patient (CT=33.5). This gene appears to be upregulated in the temporal cortex of patients with Alzheimer's disease. The temporal cortex is a region that shows severe degeneration in Alzheimer's disease, suggesting the expression of the GPCR1c gene may play a role in the pathogenesis of this disease. Therapeutic modulation of this gene or treatment with an antagonist to the receptor may be of benefit in treating Alzheimer's disease or dementia.

[0637] Ag2862 Expression is low/undetected in all samples in this panel (CT>35). (Data not shown.)

[0638] General_screening_panel_v1.5 Summary: Ag1533 Highest expression in the fetal lung (CT=30). Significant levels of expression are also detected in adult lung. This expression profile suggests that the GPCR1c gene product may be involved in the normal homeostasis of the lung. Therefore, therapeutic modulation of the expression or function of the GPCR1c gene may be effective in the treatment of diseases of that affect the lung including asthma, emphysema, and acute respiratory distress syndrome (ARDS).

[0639] The GPCR1c gene is also moderately expressed in a a variety of metabolic tissues including adipose, adult and fetal heart, adult and fetal skeletal muscle, adrenal, pituitary, thyroid and pancreas. Thus, the GPCR1c gene product may be a small molecule drug target for the treatment of metabolic disease, including obesity and Types 1 and 2 diabetes. Furthermore, the GPCR1c gene is differentially expressed in adult (CT value=37) versus fetal liver (CT values=33.5), and may be used to differentiate between the adult and fetal phenotype in this tissue.

[0640] There is moderate expression in some tissues of the central nervous system, including the fetal brain and the spinal cord. Please see CNS_neurodegeneration_v1.0 Summary for discussion of potential utility in the central nervous system.

[0641] There is also significant expression of the GPCR1c gene in a cell lines derived from ovarian cancer and gastric cancer. Please see Panel 1.2 for discussion of utility of this gene in the context of this expression profile.

[0642] Panel 1.2 Summary: Ag1533 The expression of the GPCR1c gene is highest in a sample derived from an ovarian cancer cell line (CT=29.1). Interestingly, this cell line was derived from a unique form of ovarian cancer, that being ascites. In addition, there appears to be substantial expression of the GPCR1c gene in samples derived from other ovarian cancer cell lines as well as normal bladder tissue, normal kidney tissue and a cell lined derived from a gastric cancer. Thus, the expression of this gene in these tissues could be used to distinguish these samples from other samples in the panel. Additionally, the expression of the GPCR1c gene could be used to distingush ascites derived samples from other samples in the panel. Furthermore, therapeutic modulation of this gene, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of ovarian cancer.

[0643] Panel 1.3D Summary: Ag2617 Expression is exclusive to an ovarian cancer cell line (SK-OV-3)(CT=33.1). Expression in this cell line is also detected in Panel 1.2. Interestingly, this cell line was derived from a unique form of ovarian cancer, that being ascites. Thus, the expression of the GPCR1 c gene could be used to distinguish samples derived from this cell line from other samples in the panel in addition to distingushing ascites from other samples in the panel. Moreover, therapeutic modulation of the GPCR1c gene, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of ovarian cancer.

[0644] Panel 2D Summary: Ag1533 The expression of the GPCR1c gene appears to be highest in a sample derived from normal kidney tissue (CT=31.9). In addition there is substantial expression in samples derived from other samples of normal kidney tissue adjacent to malignant kidney. Moreover, there also appears to be expression associated with tissues, normal or malignant, derived from uterus, prostate, breast, bladder and thyroid. Thus, the expression of this gene could be used to distinguish samples derived from these tissue types when compared to other samples in the panel. Further, therapeutic modulation of the GPCR1c gene, or gene product, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of cancers of the above listed tissues.

[0645] Panel 4.1D Summary: Ag1533 The GPCR1c transcript is expressed on most tissues in panel 4.1 D regardless of treatment, with highest expression in the thymus(CT=32.8). This transcript encodes a GPCR-like molecule with potential signaling activity and may important in maintaining normal cellular functions in a number of tissues. Therapies designed with the protein encoded for by this transcript could be important in regulating cellular viability or function.

[0646] Panel 4D Summary: Ag2862 The GPCR1c transcript appears to be expressed in this panel regardless of treatment, with highest expression in the kidney (CT=33.2).This transcript encodes a GPCR-like molecule with potential signaling activity and may important in maintaining normal cellular functions in a number of tissues. Therapies designed with the protein encoded for by this transcript could be important in regulating cellular viability or function.

[0647] GPCR2 (GPCR2a and GPCR2b)

[0648] Expression of the GPCR2 genes (also referred to as CG50147-01 and variant AC011711_da2) was assessed using the primer-probe sets Ag2322, Ag2365 and Ag2350, described in Tables 35, 36 and 37. Results of the RTQ-PCR runs are shown in Tables 38, 39 and 40. TABLE 35 Probe Name Ag2322 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-atcccactgtgcttcatgtatc-3′ 22 119 134 Probe TET-5′-atcccgggcaactgcacaattctttt-3′-TAMRA 26 149 135 Reverse 5′-agtgagcgctctgttttaatga-3′ 22 177 136

[0649] TABLE 36 Probe Name Ag2365 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-atcccactgtgcttcatgtatc-3′ 22 119 137 Probe TET-5′-atcccgggcaactgcacaattctttt-3′-TAMRA 26 149 138 Reverse 5′-agtgagcgctctgttttaatga-3′ 22 177 139

[0650] TABLE 37 Probe Name Ag2350 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-atcccactgtgcttcatgtatc-3′ 22 119 140 Probe TET-5′-atcccgggcaactgcacaattcttt-3′-TAMRA 26 149 141 Reverse 5′-agtgagcgctctgttttaatga-3′ 22 177 142

[0651] TABLE 38 Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Ag2322, Run Ag2350, Run Ag2322, Run Ag2350, Run Tissue Name 165627868 165974845 Tissue Name 165627868 165974845 Liver 0.0 0.0 Kidney (fetal) 0.0 0.0 adenocarcinoma Pancreas 0.0 0.0 Renal ca. 786- 0.0 0.0 0 Pancreatic ca. 0.0 0.0 Renal ca. 0.0 0.0 CAPAN 2 A498 Adrenal gland 0.0 0.0 Renal ca. RXF 0.0 0.0 393 Thyroid 0.0 0.0 Renal ca. 0.0 0.0 ACHN Salivary gland 0.0 0.0 Renal ca. UO- 0.0 0.0 31 Pituitary gland 0.0 7.6 Renal ca. TK- 0.0 0.0 10 Brain (fetal) 0.0 0.0 Liver 0.0 0.0 Brain (whole) 0.0 0.0 Liver (fetal) 0.0 0.0 Brain (amygdala) 0.0 0.0 Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain 0.0 0.0 Lung 0.0 0.0 (cerebellum) Brain 0.0 0.0 Lung (fetal) 0.0 0.0 (hippocampus) Brain (substantia 0.0 0.0 Lung ca. 0.0 0.0 nigra) (small cell) LX-1 Brain (thalamus) 0.0 0.0 Lung ca. 0.0 31.2 (small cell) NCI-H69 Cerebral Cortex 0.0 0.0 Lung ca. 100.0 100.0 (s. cell var.) SHP-77 Spinal cord 3.4 0.0 Lung ca. (large 0.0 0.0 cell) NCI-H460 glio/astro U87- 0.0 0.0 Lung ca. (non- 0.0 0.0 MG sm. cell) A549 glio/astro U-118- 0.0 0.0 Lung ca. (non- 0.0 0.0 MG s. cell) NCI- H23 astrocytoma 0.0 0.0 Lung ca. (non- 0.0 0.0 SW1783 s. cell) HOP-62 neuro*; met SK- 0.0 0.0 Lung ca. (non- 0.0 0.0 N-AS s. cl) NCI- H522 astrocytoma SF- 0.0 0.0 Lung ca. 0.0 0.0 539 (squam.) SW 900 astrocytoma 0.0 0.0 Lung ca. 16.6 15.5 SNB-75 (squam.) NCI- H596 Glioma SNB-19 2.5 0.0 Mammary 0.0 0.0 gland Glioma U251 0.0 0.0 Breast ca.* 0.0 0.0 (pl. ef) MCF-7 Glioma SF-295 0.0 0.0 Breast ca.* 0.0 0.0 (pl. ef) MDA- MB-231 Heart (Fetal) 0.0 0.0 Breast ca.* (pl. 0.0 0.0 ef) T47D Heart 0.0 0.0 Breast ca. BT- 0.0 0.0 549 Skeletal muscle 0.0 0.0 Breast ca. 0.0 0.0 (Fetal) MDA-N Skeletal muscle 0.0 0.0 Ovary 0.0 0.0 Bone marrow 0.0 0.0 Ovarian ca. 1.7 0.0 OVCAR-3 Thymus 0.0 0.0 Ovarian ca. 0.0 0.0 OVCAR-4 Spleen 0.0 0.0 Ovarian ca. 0.0 0.0 OVCAR-5 Lymph node 0.0 0.0 Ovarian ca. 0.0 4.8 OVCAR-8 Colorectal 1.4 0.0 Ovarian ca. 0.0 0.0 IGROV-1 Stomach 0.0 0.0 Ovarian ca. 0.0 0.0 (ascites) SK- OV-3 Small intestine 0.0 0.0 Uterus 0.0 0.0 Colon ca. SW480 0.0 0.0 Placenta 0.0 0.0 Colon ca.* 0.0 0.0 Prostate 0.0 0.0 SW620 (SW480 met) Colon ca. HT29 0.0 0.0 Prostate ca.* 0.0 0.0 (bone met) PC-3 Colon ca. HCT- 0.0 0.0 Testis 0.0 0.0 116 Colon ca. CaCo-2 0.0 0.0 Melanoma 0.0 0.0 Hs688(A).T CC Well to Mod 0.0 0.0 Melanoma* 0.0 0.0 Diff (ODO3866) (met) Hs688(B).T Colon ca. HCC- 0.0 0.0 Melanoma 0.0 0.0 2998 UACC-62 Gastric ca. (liver 3.3 0.0 Melanoma 0.0 0.0 met) NCI-N87 M14 Bladder 0.0 6.9 Melanoma 0.0 0.0 LOX IMVI Trachea 0.0 0.0 Melanoma* 0.0 0.0 (met) SK- MEL-5 Kidney 0.0 0.0 Adipose 0.0 0.0

[0652] TABLE 39 Panel 2D Rel. Exp. (%) Ag2350, Rel. Exp. (%) Ag2350, Tissue Name Run 164079723 Tissue Name Run 164079723 Normal Colon 7.6 Kidney Margin 0.0 8120608 CC Well to Mod Diff 4.1 Kidney Cancer 0.0 (ODO3866) 8120613 CC Margin (ODO3866) 1.5 Kidney Margin 0.0 8120614 CC Gr.2 rectosigmoid 3.0 Kidney Cancer 0.0 (ODO3868) 9010320 CC Margin (ODO3868) 0.0 Kidney Margin 0.0 9010321 CC Mod Diff (ODO3920) 0.0 Normal Uterus 0.0 CC Margin (ODO3920) 7.1 Uterine Cancer 3.7 064011 CC Gr.2 ascend colon 0.0 Normal Thyroid 0.0 (ODO3921) CC Margin (ODO3921) 0.0 Thyroid Cancer 0.0 CC from Partial 0.0 Thyroid Cancer 0.0 Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.0 Thyroid Margin 0.0 A302153 Colon mets to lung 0.0 Normal Breast 0.0 (OD04451-01) Lung Margin 0.0 Breast Cancer 7.6 (OD04451-02) Normal Prostate 6546-1 22.4 Breast Cancer 0.0 (OD04590-01) Prostate Cancer 74.7 Breast Cancer Mets 0.0 (OD04410) (OD04590-03) Prostate Margin 100.0 Breast Cancer 0.0 (OD04410) Metastasis Prostate Cancer 30.1 Breast Cancer 0.0 (OD04720-01) Prostate Margin 38.7 Breast Cancer 0.0 (OD04720-02) Normal Lung 0.0 Breast Cancer 0.0 9100266 Lung Met to Muscle 0.0 Breast Margin 1.7 (ODO4286) 9100265 Muscle Margin 0.0 Breast Cancer 7.2 (ODO4286) A209073 Lung Malignant Cancer 25.5 Breast Margin 0.0 (OD03126) A2090734 Lung Margin (OD03126) 0.0 Normal Liver 0.0 Lung Cancer (OD04404) 6.5 Liver Cancer 0.0 Lung Margin (OD04404) 0.0 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 0.0 Liver Cancer 1026 0.0 Lung Margin (OD04565) 0.0 Liver Cancer 6004-T 0.0 Lung Cancer (OD04237-01) 0.0 Liver Tissue 6004-N 0.0 Lung Margin (OD04237-02) 0.0 Liver Cancer 6005-T 0.0 Ocular Mel Met to Liver 0.0 Liver Tissue 6005-N 0.0 (ODO4310) Liver Margin (ODO4310) 0.0 Normal Bladder 0.0 Melanoma Metastasis 0.0 Bladder Cancer 0.0 Lung Margin (OD04321) 0.0 Bladder Cancer 6.1 Normal Kidney 0.0 Bladder Cancer 0.0 (OD04718-01) Kidney Ca, Nuclear grade 0.0 Bladder Normal 0.0 2 (OD04338) Adjacent (OD04718-03) Kidney Margin 3.6 Normal Ovary 0.0 (OD04338) Kidney Ca Nuclear grade 0.0 Ovarian Cancer 0.0 ½ (OD04339) Kidney Margin 0.0 Ovarian Cancer 0.0 (OD04339) (OD04768-07) Kidney Ca, Clear cell 0.0 Ovary Margin 0.0 type (OD04340) (OD04768-08) Kidney Margin 0.0 Normal Stomach 0.0 (OD04340) Kidney Ca, Nuclear grade 1.7 Gastric Cancer 0.0 3 (OD04348) 9060358 Kidney Margin 0.0 Stomach Margin 0.0 (OD04348) 9060359 Kidney Cancer 0.0 Gastric Cancer 0.0 (OD04622-01) 9060395 Kidney Margin 0.0 Stomach Margin 0.0 (OD04622-03) 9060394 Kidney Cancer 0.0 Gastric Cancer 0.0 (OD04450-01) 9060397 Kidney Margin 0.0 Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 8120607 0.0 Gastric Cancer 3.7 064005

[0653] TABLE 40 Panel 4D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Ag2322, Run Ag2350, Run Ag2322, Run Ag2350, Run Tissue Name 162360932 164145590 Tissue Name 162360932 164145590 Secondary Th1 act 0.0 0.0 HUVEC IL-1beta 0.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN 0.0 0.0 gamma Secondary Tr1 act 0.0 29.3 HUVEC TNF 0.0 0.0 alpha + IFN gamma Secondary Th1 rest 0.0 0.0 HUVEC TNF 0.0 0.0 alpha + IL4 Secondary Th2 rest 0.0 0.0 HUVEC IL-11 0.0 0.0 Secondary Tr1 rest 0.0 0.0 Lung 0.0 0.0 Microvascular EC none Primary Th1 act 0.0 0.0 Lung 0.0 0.0 Microvascular EC TNFalpha + IL- 1beta Primary Th2 act 0.0 0.0 Microvascular 0.0 0.0 Dermal EC none Primary Tr1 act 0.0 0.0 Microsvasular 0.0 0.0 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 0.0 0.0 Bronchial 0.0 0.0 epithelium TNFalpha + IL1beta Primary Th2 rest 0.0 0.0 Small airway 0.0 0.0 epithelium none Primary Tr1 rest 0.0 0.0 Small airway 0.0 0.0 epithelium TNFalpha + IL- 1beta CD45RA CD4 0.0 0.0 Coronery artery 0.0 0.0 lymphocyte act SMC rest CD45RO CD4 0.0 0.0 Coronery artery 0.0 48.0 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 0.0 23.3 Astrocytes rest 0.0 0.0 act Secondary CD8 0.0 0.0 Astrocytes 0.0 0.0 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 21.2 0.0 KU-812 0.0 0.0 lymphocyte act (Basophil) rest CD4 lymphocyte 0.0 0.0 KU-812 0.0 0.0 none (Basophil) PMA/ionomycin 2ry 0.0 0.0 CCD1106 0.0 0.0 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 0.0 CCD1106 0.0 0.0 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 0.0 0.0 Liver cirrhosis 100.0 100.0 LAK cells IL-2 + IL- 0.0 0.0 Lupus kidney 0.0 0.0 12 LAK cells IL- 0.0 0.0 NCI-H292 0.0 0.0 2 + IFN gamma none LAK cells IL-2 + 0.0 0.0 NCI-H292 IL-4 0.0 0.0 IL-18 LAK cells 0.0 0.0 NCI-H292 IL-9 0.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 NCI-H292 IL-13 0.0 0.0 Two Way MLR 3 0.0 0.0 NCI-H292 IFN 0.0 0.0 day gamma Two Way MLR 5 0.0 0.0 HPAEC none 0.0 0.0 day Two Way MLR 7 0.0 0.0 HPAEC TNF 0.0 0.0 day alpha + IL-1 beta PBMC rest 0.0 0.0 Lung fibroblast 0.0 21.0 none PBMC PWM 0.0 0.0 Lung fibroblast 0.0 0.0 TNF alpha + IL-1 beta PBMC PHA-L 0.0 0.0 Lung fibroblast 0.0 0.0 IL-4 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 none IL-9 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 ionomycin IL-13 B lymphocytes 7.1 0.0 Lung fibroblast 0.0 40.1 PWM IFN gamma B lymphocytes 0.0 0.0 Dermal fibroblast 0.0 0.0 CD40L and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells 0.0 0.0 Dermal fibroblast 0.0 0.0 none IFN gamma Dendritic cells LPS 0.0 0.0 Dermal fibroblast 0.0 0.0 IL-4 Dendritic cells anti- 0.0 0.0 IBD Colitis 2 43.2 19.2 CD40 Monocytes rest 0.0 0.0 IBD Crohn's 0.0 15.3 Monocytes LPS 0.0 0.0 Colon 0.0 0.0 Macrophages rest 0.0 0.0 Lung 0.0 0.0 Macrophages LPS 0.0 0.0 Thymus 0.0 19.1 HUVEC none 0.0 0.0 Kidney 0.0 0.0 HUVEC starved 0.0 0.0

[0654] CNS_neurodegeneration_v1.0 Summary: Ag2365 Expression is low/undetectable in all samples in this panel due to a probable probe failure. (Data not shown.)

[0655] Panel 1.3D Summary: Ag2322/2350 Expression of the GPCR2 genes is concordant in two runs with the same probe and primer set. In both runs, a sample derived from a small cell lung cancer cell line (SHP-77) showed the highest expression (CTs=32-33). There is apparent expression in other small cell lung cancer cell lines as well. Thus, the expression of the GPCR2 genes could be used to distinguish SHP-77 cells and other small cell lung cancer cell lines from other samples on the panel. Furthermore, therapeutic modulation of the expression of the GPCR2 genes, through the use of small molecule drugs, antibodies or protein therapeutics may be of use in the treatment of small cell lung cancer.

[0656] Please note that expression is low/undetectable in all samples in this panel (CTs>35) in a third experiment run with Ag2365. (Data not shown.)

[0657] Panel 2D Summary: Ag2350 The expression of the GPCR2 genes is highest in a sample derived from normal prostate tissue adjacent to a prostate cancer(CT=32.3). This pattern is true for a second matched pair of prostate cancer and normal tissue, as well. This pattern of expression appears to be highly specific and thus the expression of the GPCR2 genes could be used to distinguish prostate derived tissues from other tissues in the panel.

[0658] Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, antibodies or protein therapeutics may be beneficial in the treatment of prostate cancer.

[0659] Panel 3D Summary: Ag2350 The amp plot from one experiment with this probe and primer set suggests that there were experimental difficulties with this run. (Data not shown.)

[0660] Panel 4D Summary: Ag2322/Ag2350 Significant expression of the GPCR2 genes is restricted to liver cirrhosis (CTs=34-35). Furthermore, the transcript is not expressed in normal liver in panel 1.3D or 2D. Thus, expression of the GPCR2 genes could be used for detection of liver cirrhosis. The putative GPCR encoded by this transcript may also play an important role in liver cirrhosis. Therefore, therapeutics designed with the protein encoded for by this transcript could be important for maintaining or restoring normal function to the liver undergoing cirrhosis.

[0661] GPCR3

[0662] Expression of the GPCR3 gene (also referred to as GMAC024428_A and variant CG92194_(—)01) was assessed using the primer-probe sets Ag2265, Ag2266 and Ag2277, described in Tables 41, 42 and 43. Results of the RTQ-PCR runs are shown in Tables 44 and 45. TABLE 41 Probe Name Ag2265 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-ctctcttctgtggaatcattgc-3′ 22 914 143 Probe TET-5′-cccatgctgaatccccttatatataca-3′-TAMRA 27 937 144 Reverse 5′-ggcttcctttacctctttgttc-3′ 22 969 145

[0663] TABLE 42 Probe Name Ag2266 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-agattccaccctttgtgatgtt-3′ 22 161 146 Probe TET-5′-tcttgacaatctttggcaatctgaca-3′-TAMRA 26 197 147 Reverse 5′-tgaaatccacatgtgacacaag-3′ 22 229 148

[0664] TABLE 43 Probe Name Ag2277 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-agattccaccctttgtgatgtt-3′ 22 161 149 Probe TET-5′-tcttgacaatctttggcaatctgaca-3′ 26 197 150 Reverse 5′-tgaaatccacatgtgacacaag-3′ 22 229 151

[0665] TABLE 44 Panel 1.3D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag2265, Ag2266, Ag2277, Ag2265, Ag2266, Ag2277, Run Run Run Run Run Run Tissue Name 151562862 151041217 151769293 Tissue Name 151562862 151041217 151769293 Liver 3.3 1.0 4.7 Kidney 2.7 0.0 0.0 adenocarcinoma (fetal) Pancreas 2.8 0.0 0.0 Renal ca. 3.6 0.0 2.3 786-0 Pancreatic ca. 0.0 0.0 0.0 Renal ca. 7.6 8.6 5.0 CAPAN 2 A498 Adrenal gland 0.0 1.0 0.0 Renal ca. 1.4 0.0 0.0 RXF 393 Thyroid 0.0 1.2 0.0 Renal ca. 0.0 0.0 0.0 ACHN Salivary gland 0.0 0.0 0.0 Renal ca. 0.0 0.0 0.0 UO-31 Pituitary gland 0.0 0.0 0.0 Renal ca. 0.0 0.6 0.0 TK-10 Brain (fetal) 0.0 1.0 0.0 Liver 0.0 3.4 0.0 Brain (whole) 0.0 0.0 0.0 Liver (fetal) 7.7 2.1 7.3 Brain 0.0 0.0 0.0 Liver ca. 6.3 0.0 2.8 (amygdala) (hepatoblast) HepG2 Brain 0.0 0.0 2.0 Lung 0.0 0.0 0.0 (cerebellum) Brain 0.0 0.6 0.0 Lung (fetal) 1.7 0.6 0.0 (hippocampus) Brain 1.4 0.0 0.0 Lung ca. 7.9 1.3 0.7 (substantia (small cell) nigra) LX-1 Brain 0.0 0.0 0.0 Lung ca. 11.7 3.5 5.3 (thalamus) (small cell) NCI-H69 Cerebral Cortex 0.5 0.2 0.0 Lung ca. 33.0 22.1 12.8 (s. cell var.) SHP-77 Spinal cord 1.2 0.0 0.0 Lung ca. 1.3 0.0 0.0 (large cell) NCI- H460 glio/astro U87- 4.1 3.2 2.9 Lung ca. 0.0 0.0 0.0 MG (non-sm. cell) A549 glio/astro U- 12.2 9.2 32.8 Lung ca. 36.3 16.3 15.9 118-MG (non-s. cell) NCI-H23 astrocytoma 1.0 6.0 0.0 Lung ca. 0.0 3.2 0.0 SW1783 (non-s. cell) HOP-62 neuro*; met 15.8 6.6 9.2 Lung ca. 14.6 3.4 3.0 SK-N-AS (non-s. cl) NCI-H522 astrocytoma 2.2 1.8 0.0 Lung ca. 0.0 1.2 1.6 SF-539 (squam.) SW 900 astrocytoma 6.3 13.5 6.0 Lung ca. 13.0 16.5 1.8 SNB-75 (squam.) NCI-H596 Glioma SNB-19 0.0 0.0 0.0 Mammary 0.0 1.0 0.0 gland Glioma U251 0.0 0.0 0.0 Breast ca.* 72.2 90.8 100.0 (pl. ef) MCF- 7 Glioma SF-295 8.8 4.6 8.7 Breast ca.* 26.1 31.0 7.0 (pl. ef) MDA-MB- 231 Heart (Fetal) 0.0 0.0 0.0 Breast ca.* 3.4 6.1 2.4 (pl. ef) T47D Heart 0.0 0.0 1.9 Breast ca. 11.0 8.6 7.9 BT-549 Skeletal muscle 1.3 3.1 0.0 Breast ca. 6.6 16.6 6.9 (Fetal) MDA-N Skeletal muscle 0.0 0.0 2.4 Ovary 0.0 0.0 0.0 Bone marrow 6.4 4.7 5.9 Ovarian ca. 11.5 15.5 7.4 OVCAR-3 Thymus 0.0 2.7 2.3 Ovarian ca. 0.0 0.0 0.0 OVCAR-4 Spleen 0.0 1.1 1.3 Ovarian ca. 2.2 5.0 6.4 OVCAR-5 Lymph node 0.0 0.0 0.0 Ovarian ca. 1.4 0.8 0.0 OVCAR-8 Colorectal 2.4 1.8 1.8 Ovarian ca. 2.6 0.0 0.0 IGROV-1 Stomach 0.0 2.4 4.9 Ovarian ca. 0.0 1.1 0.0 (ascites) SK- OV-3 Small intestine 3.3 1.1 2.5 Uterus 0.0 0.0 0.0 Colon ca. 12.8 8.2 16.4 Placenta 5.7 5.8 12.2 SW480 Colon ca.* 7.2 3.1 7.5 Prostate 4.3 0.0 0.0 SW620 (SW480 met) Colon ca. HT29 2.3 5.1 5.1 Prostate ca.* 8.2 7.8 10.9 (bone met) PC-3 Colon ca. HCT- 0.0 5.0 1.8 Testis 3.8 4.4 7.4 116 Colon ca. 13.8 1.6 4.1 Melanoma 0.0 0.5 0.0 CaCo-2 Hs688(A).T CC Well to 0.0 0.0 0.0 Melanoma* 0.0 0.0 0.0 Mod Diff (met) (ODO3866) Hs688(B).T Colon ca. HCC- 6.7 9.0 11.0 Melanoma 0.0 0.0 0.0 2998 UACC-62 Gastric ca. 100.0 100.0 64.2 Melanoma 3.2 1.1 1.6 (liver met) NCI- M14 N87 Bladder 2.3 0.7 2.4 Melanoma 1.9 0.0 0.0 LOX IMVI Trachea 3.7 1.9 0.0 Melanoma* 0.0 1.1 0.0 (met) SK- MEL-5 Kidney 0.0 0.0 0.0 Adipose 0.0 0.0 0.0

[0666] TABLE 45 Panel 4D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag2265, Ag2266, Ag2277, Ag2265, Ag2266, Ag2277, Run Run Run Run Run Run Tissue Name 166778536 166897525 166818127 Tissue Name 166778536 166897525 166818127 Secondary Th1 act 17.1 6.7 3.4 HUVEC IL- 0.0 0.0 0.0 1beta Secondary Th2 act 7.1 0.0 2.5 HUVEC IFN 0.0 0.0 0.0 gamma Secondary Tr1 act 4.9 4.0 0.0 HUVEC TNF 0.0 0.0 0.0 alpha + IFN gamma Secondary Th1 19.6 3.9 1.0 HUVEC TNF 0.0 0.0 0.0 rest alpha + IL4 Secondary Th2 6.9 4.5 0.0 HUVEC IL-11 0.0 0.0 0.0 rest Secondary Tr1 7.1 0.0 6.5 Lung 0.0 0.0 0.0 rest Microvascular EC none Primary Th1 act 3.1 1.9 0.0 Lung 4.3 0.0 0.0 Microvascular EC TNFalpha + IL-1beta Primary Th2 act 6.0 3.8 0.0 Microvascular 0.0 0.0 0.0 Dermal EC none Primary Tr1 act 0.0 4.2 4.9 Microsvasular 0.0 0.0 2.1 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 12.9 10.4 2.6 Bronchial 0.0 0.0 51.8 epithelium TNFalpha + IL1beta Primary Th2 rest 3.4 3.0 2.9 Small airway 0.0 0.0 49.7 epithelium none Primary Tr1 rest 12.0 3.8 0.0 Small airway 0.0 0.0 11.4 epithelium TNFalpha + IL- 1beta CD45RA CD4 5.2 0.0 7.3 Coronery artery 2.0 0.0 0.0 lymphocyte act SMC rest CD45RO CD4 0.0 0.0 3.0 Coronery artery 0.0 0.0 1.8 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 2.6 4.0 3.9 Astrocytes rest 0.0 0.0 2.7 act Secondary CD8 4.5 0.0 0.0 Astrocytes 0.0 9.6 0.0 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 1.9 0.0 0.0 KU-812 10.1 47.6 16.5 lymphocyte act (Basophil) rest CD4 lymphocyte 0.0 0.0 0.5 KU-812 79.6 100.0 100.0 none (Basophil) PMA/ionomycin 2ry 10.0 4.6 2.7 CCD1106 8.7 0.0 13.1 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 0.0 2.0 CCD1106 2.3 0.0 0.0 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 12.5 6.7 8.1 Liver cirrhosis 5.3 0.0 4.1 LAK cells IL- 2.3 0.0 2.1 Lupus kidney 0.0 0.0 0.2 2 + IL-12 LAK cells IL- 10.2 5.6 7.6 NCI-H292 none 0.0 9.3 2.9 2 + IFN gamma LAK cells IL-2 + 16.5 9.9 4.4 NCI-H292 IL-4 6.2 1.6 5.8 IL-18 LAK cells 0.0 0.0 0.0 NCI-H292 IL-9 3.2 10.3 6.0 PMA/ionomycin NK Cells IL-2 rest 0.0 16.0 5.6 NCI-H292 IL-13 0.0 5.0 12.2 Two Way MLR 3 0.0 0.0 0.0 NCI-H292 IFN 2.2 14.0 7.4 day gamma Two Way MLR 5 5.5 8.8 0.0 HPAEC none 0.0 0.0 0.0 day Two Way MLR 7 0.0 14.7 2.3 HPAEC TNF 0.0 0.0 2.3 day alpha + IL-1 beta PBMC rest 0.0 0.0 0.0 Lung fibroblast 1.7 5.6 0.0 none PBMC PWM 57.8 45.1 40.9 Lung fibroblast 0.0 0.0 3.5 TNF alpha + IL- 1 beta PBMC PHA-L 5.2 3.6 0.0 Lung fibroblast 0.0 0.0 0.0 IL-4 Ramos (B cell) 6.1 0.0 2.4 Lung fibroblast 0.0 0.0 0.0 none IL-9 Ramos (B cell) 12.7 39.0 2.1 Lung fibroblast 2.3 0.0 0.0 ionomycin IL-13 B lymphocytes 25.3 42.3 29.5 Lung fibroblast 0.0 0.0 2.5 PWM IFN gamma B lymphocytes 7.9 17.9 2.3 Dermal 1.7 0.0 2.3 CD40L and IL-4 fibroblast CCD1070 rest EOL-1 dbcAMP 0.0 0.0 0.0 Dermal 8.1 14.5 11.4 fibroblast CCD1070 TNF alpha EOL-1 dbcAMP 0.0 4.4 0.0 Dermal 0.0 4.9 1.5 PMA/ionomycin fibroblast CCD1070 IL-1 beta Dendritic cells 0.0 0.0 0.0 Dermal 2.7 0.0 0.0 none fibroblast IFN gamma Dendritic cells 0.0 0.0 0.0 Dermal 2.0 7.5 7.7 LPS fibroblast IL-4 Dendritic cells 0.0 0.0 0.0 IBD Colitis 2 0.0 0.0 6.8 anti-CD40 Monocytes rest 0.0 0.0 0.0 IBD Crohn's 2.9 4.6 0.0 Monocytes LPS 0.0 10.7 0.0 Colon 0.0 0.0 0.0 Macrophages rest 0.0 0.0 0.0 Lung 0.0 0.0 2.9 Macrophages LPS 0.0 0.0 0.0 Thymus 0.0 0.0 0.0 HUVEC none 0.0 0.0 0.0 Kidney 100.0 81.2 48.0 HUVEC starved 0.0 0.0 3.1

[0667] Panel 1.3D Summary: Ag2265/2266/2277 The expression of the GPCR3 gene was assessed in triplicate runs on panel 1.3D. There was good concordance between runs, with the highest expression seen in cell lines derived from a gastric cancer metastasis (NCI-N87) (CTs=30.5-32.5) and breast cancer (MCF-7). Thus, the expression of the GPCR3 gene could be used to distinguish NCI-N87 and MCF-7 from the other samples in the panel. Moreover, therapeutic modulation of the GPCR3 genes, through the use of small molecule drugs, antibodies or protein therapeutics might be of benefit in the treatment of gastric cancer or breast cancer.

[0668] Panel 2.2 Summary: Ag2265/2266/2277 Expression is low/undetectable in all samples in this panel. (CTs>35). (Data not shown.)

[0669] Panel 4D Summary: Ag2265/2266/2277 The GPCR3 gene is expressed in normal kidney and in a basophil cell line and is slightly induced in activated basophils. Basophils are an important component of the allergic immune response. These cells produce cytokines and mediators that can activate T cells (IL-4), induce eosinophil recruitment, smooth muscle contraction, and vascular permeability (histamines) and contribute to tissue destruction (IL-13) (1). Therefore, therapeutics designed to block the function of the protein encoded by this transcript could be important in the treatment of asthma, inflammatory bowel disease and psoriasis.

[0670] GPCR4

[0671] Expression of GPCR4 (also referred to as CG50169-01) was assessed using the primer-probe sets Ag2384, Ag2226 and Agl 828, described in Tables 46, 47 and 48. Results of the RTQ-PCR runs are shown in Tables 49 and 50. TABLE 46 Probe Name Ag2384 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-ggaaagtgtcctccctgttcta-3′ 22 824 152 Probe TET-5′-ccataatagtccccgtgttaaaccca-3′ 26 48 153 Reverse 5′-ctttgacatccttgttcctcaa-3′ 22 886 154

[0672] TABLE 47 Probe Name Ag2226 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-ggaaagtgtcctccctgttcta-3′ 22 824 155 Probe TET-5′-ccataatagtccccgtgttaaaccca-3′-TAMRA 26 848 156 Reverse 5′-ctttgacatccttgttcctcaa-3′ 22 886 157

[0673] TABLE 48 Probe Name Ag1828 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-cctctccagcattctacacaac-3′ 22 675 158 Probe TET-5′-tctacagaaggcaggtccaaagcctt-3′-TAMRA 26 700 159 Reverse 5′-caattatgtgggaactgcaagt-3′ 22 730 160

[0674] TABLE 49 Panel 1.3D Rel. Exp. (%) Ag2384, Rel. Exp. (%) Ag2384, Tissue Name Run 165629298 Tissue Name Run 165629298 Liver adenocarcinoma 10.5 Kidney (fetal) 9.5 Pancreas 1.3 Renal ca. 786-0 2.9 Pancreatic ca. 3.7 Renal ca. A498 5.0 CAPAN 2 Adrenal gland 5.8 Renal ca. RXF 393 8.6 Thyroid 23.7 Renal ca. ACHN 6.1 Salivary gland 4.6 Renal ca. UO-31 2.3 Pituitary gland 5.6 Renal ca. TK-10 1.9 Brain (fetal) 7.6 Liver 1.3 Brain (whole) 2.4 Liver (fetal) 5.3 Brain (amygdala) 7.6 Liver ca. 0.1 (hepatoblast) HepG2 Brain (cerebellum) 1.1 Lung 17.9 Brain (hippocampus) 6.2 Lung (fetal) 15.0 Brain (substantia nigra) 2.8 Lung ca. (small cell) 2.3 LX-1 Brain (thalamus) 4.8 Lung ca. (small cell) 0.1 NCI-H69 Cerebral Cortex 2.8 Lung ca. (s. cell var.) 5.8 SHP-77 Spinal cord 13.9 Lung ca. (large 4.8 cell) NCI-H460 glio/astro U87-MG 1.5 Lung ca. (non-sm. 1.5 cell) A549 glio/astro U-118-MG 4.2 Lung ca. (non-s. cell) 3.1 NCI-H23 astrocytoma SW1783 0.1 Lung ca. (non-s. cell) 3.9 HOP-62 neuro*; met SK-N-AS 4.0 Lung ca. (non-s. cl) 1.8 NCI-H522 astrocytoma SF-539 3.5 Lung ca. (squam.) 9.3 SW 900 astrocytoma SNB-75 12.1 Lung ca. (squam.) 0.0 NCI-H596 Glioma SNB-19 8.3 Mammary gland 15.4 Glioma U251 3.8 Breast ca.* (pl. ef) 7.1 MCF-7 Glioma SF-295 5.2 Breast ca.* (pl. ef) 12.5 MDA-MB-231 Heart (Fetal) 15.5 Breast ca.* (pl. ef) 1.8 T47D Heart 20.6 Breast ca. BT-549 2.4 Skeletal muscle (Fetal) 8.0 Breast ca. MDA-N 0.7 Skeletal muscle 13.2 Ovary 51.8 Bone marrow 1.1 Ovarian ca. OVCAR-3 0.7 Thymus 2.2 Ovarian ca. OVCAR-4 4.4 Spleen 11.0 Ovarian ca. OVCAR-5 4.4 Lymph node 21.3 Ovarian ca. OVCAR-8 0.6 Colorectal 5.4 Ovarian ca. IGROV-1 0.6 Stomach 19.2 Ovarian ca. (ascites) 1.2 SK-OV-3 Small intestine 60.7 Uterus 100.0 Colon ca. SW480 0.6 Placenta 4.5 Colon ca.* SW620 0.4 Prostate 8.1 (SW480 met) Colon ca. HT29 0.3 Prostate ca.* (bone 3.2 met) PC-3 Colon ca. HCT-116 5.3 Testis 17.9 Colon ca. CaCo-2 1.3 Melanoma 0.6 Hs688 (A).T CC Well to Mod Diff 2.5 Melanoma* (met) 0.2 (ODO3866) Hs688 (B).T Colon ca. HCC-2998 2.7 Melanoma UACC-62 0.9 Gastric ca. (liver met) 6.4 Melanoma M14 5.3 NCI-N87 Bladder 2.5 Melanoma LOX 1.6 IMVI Trachea 24.5 Melanoma* (met) 1.8 SK-MEL-5 Kidney 2.2 Adipose 7.2

[0675] TABLE 50 Panel 4D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Ag1828, Run Ag2384, Run Ag1828, Run Ag2384, Run Tissue Name 165810353 162321123 Tissue Name 165810353 162321123 Secondary Th1 act 0.0 10.9 HUVEC IL-1beta 0.0 4.8 Secondary Th2 act 0.0 14.7 HUVEC IFN 0.0 15.6 gamma Secondary Tr1 act 0.0 11.6 HUVEC TNF 0.0 23.8 alpha + IFN gamma Secondary Th1 rest 0.0 6.6 HUVEC TNF 0.0 24.8 alpha + IL4 Secondary Th2 rest 0.0 12.9 HUVEC IL-11 0.0 14.0 Secondary Tr1 rest 0.0 8.4 Lung 0.0 27.9 Microvascular EC none Primary Th1 act 0.0 8.2 Lung 0.0 17.7 Microvascular EC TNFalpha + IL- 1beta Primary Th2 act 0.0 20.3 Microvascular 0.0 22.1 Dermal EC none Primary Tr1 act 22.7 17.4 Microsvasular 0.0 15.8 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 0.0 22.7 Bronchial 0.0 17.4 epithelium TNFalpha + IL1beta Primary Th2 rest 3.5 16.0 Small airway 0.0 7.3 epithelium none Primary Tr1 rest 0.0 15.8 Small airway 0.0 34.6 epithelium TNFalpha + IL- 1beta CD45RA CD4 0.0 19.3 Coronery artery 0.0 81.8 lymphocyte act SMC rest CD45RO CD4 0.0 8.8 Coronery artery 0.0 41.8 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 0.0 9.0 Astrocytes rest 0.0 34.2 act Secondary CD8 0.0 7.9 Astrocytes 0.0 26.1 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 0.0 11.2 KU-812 0.0 13.7 lymphocyte act (Basophil) rest CD4 lymphocyte 0.0 9.2 KU-812 6.9 35.6 none (Basophil) PMA/ionomycin 2ry 0.0 14.8 CCD1106 0.0 19.3 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 16.8 CCD1106 0.0 23.7 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 0.0 5.1 Liver cirrhosis 100.0 4.1 LAK cells IL-2 + IL- 0.0 8.1 Lupus kidney 0.0 3.0 12 LAK cells IL- 0.0 9.0 NCI-H292 none 0.0 0.0 2 + IFN gamma LAK cells IL-2 + 0.0 8.7 NCI-H292 IL-4 0.0 0.0 IL-18 LAK cells 0.0 27.5 NCI-H292 IL-9 0.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 6.9 NCI-H292 IL-13 0.0 0.0 Two Way MLR 3 0.0 6.6 NCI-H292 IFN 0.0 0.0 day gamma Two Way MLR 5 0.0 7.1 HPAEC none 0.0 9.7 day Two Way MLR 7 0.0 6.2 HPAEC TNF 0.0 13.2 day alpha + IL-1 beta PBMC rest 0.0 21.2 Lung fibroblast 0.0 23.5 none PBMC PWM 0.0 10.7 Lung fibroblast 0.0 6.8 TNF alpha + IL-1 beta PBMC PHA-L 0.0 15.0 Lung fibroblast 0.0 61.1 IL-4 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 29.7 none IL-9 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 37.4 ionomycin IL-13 B lymphocytes 0.0 17.6 Lung fibroblast 0.0 64.2 PWM IFN gamma B lymphocytes 3.8 2.3 Dermal fibroblast 0.0 100.0 CD40L and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 20.3 Dermal fibroblast 0.0 78.5 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 4.5 Dermal fibroblast 0.0 54.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells 0.0 16.3 Dermal fibroblast 0.0 26.4 none IFN gamma Dendritic cells LPS 0.0 21.5 Dermal fibroblast 0.0 42.0 IL-4 Dendritic cells anti- 7.6 24.1 IBD Colitis 2 8.1 4.3 CD40 Monocytes rest 0.0 44.8 IBD Crohn's 9.2 6.3 Monocytes LPS 0.0 3.4 Colon 31.9 30.4 Macrophages rest 3.7 34.2 Lung 3.8 33.0 Macrophages LPS 0.0 12.7 Thymus 0.0 4.0 HUVEC none 0.0 19.5 Kidney 0.0 16.8 HUVEC starved 0.0 25.5

[0676] CNS_neurodegeneration_v1.0 Summary: Ag2226/Ag2384 Expression is low/undetectable in all the samples in this panel. (CTs>35). (Data not shown.)

[0677] Panel 1.3D Summary: Ag2384 Highest expression of the GPCR4 gene is detected in the uterus (CT=28.8). There is also substantial expression in normal ovarian and small intestine tissue. Of note is the low level of expression in cell lines derived from ovarian cancer. Thus, the expression of this gene could be used to distinguish uterine, ovarian and small intestine tissue from other tissues in the panel. In addition, the expression of this gene could be used to distinguish normal ovarian tissue from samples derived from ovarian cancer cell lines. Furthermore, therapeutic modulation of the GPCR4 gene, through the use of small molecule drugs, antibodies or protein therapeutics may be beneficial in the treatment of ovarian cancer.

[0678] The GPCR4 gene is also moderately expressed (CT values=31-33)in a variety of metabolic tissues including adrenal, thyroid, pituitary, adult and fetal heart, adult and fetal skeletal muscle, fetal liver and adipose. Thus, the GPCR4 gene product may be a small molecule target for the treatment of metabolic disease, including obesity and Types 1 and 2 diabetes.

[0679] The GPCR4 gene is expressed at low to moderate levels in all CNS regions examined. The encoded protein is a novel member of the GPCR family of receptors. Several neurotransmitter receptors are GPCRs, including the dopamine receptor family, the serotonin receptor family, the GABAB receptor, muscarinic acetylcholine receptors, and others; thus, GPCR4 may represent a novel neurotransmitter receptor. Targeting various neurotransmitter receptors (dopamine, serotonin) has proven to be an effective therapy in psychiatric illnesses such as schizophrenia, bipolar disorder and depression. In addition, other regions where the GPCR4 gene is expressed (the cerebral cortex and hippocampus) are known to play critical roles in Alzheimer's disease, seizure disorders, and in the normal process of memory formation. Thus, therapeutic modulation of the expression of this gene or its protein product may be beneficial in one or more of these diseases, as may blockade of the receptor encoded by the gene. Furthermore, significant levels of expression of the GPCR4 gene in areas outside the central nervous system (such as uterus and ovary), suggest the possibility of a wider role in intercellular signaling.

[0680] Please note that a second experiment with the probe and primer set Ag2226 showed expression to be low/undetectable in all the samples in this panel. (CTs>35). (Data not shown.)

[0681] Panel 2.2 Summary: Ag2226 Expression is low/undetectable in all the samples in this panel. (CTs>35). (Data not shown.)

[0682] Panel 4D Summary: Ag2384 The GPCR4 transcript is expressed in most tissues in this panel regardless of treatment. This transcript encodes a GPCR like molecule with potential signaling activity that may be important in maintaining normal cellular functions in a number of tissues. Therapies designed with the protein encoded by this transcript could be important in regulating cellular viability or function.

[0683] A second experiment with the probe and primer set Agl 828 is not consistent with the above results and shows low levels of transcript expression in liver cirrhosis only.

[0684] Ag2226 Expression is low/undetectable in all the samples in this panel. (CTs>35). (Data not shown.)

[0685] GPCR5

[0686] Expression of the GPCR5 gene (also referred to as AC009758_da1) was assessed using the primer-probe sets Ag2319 and Ag2337, described in Tables 51 and 52. Results of the RTQ-PCR runs are shown in Table 53. TABLE 51 Probe Name Ag2319 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-attccacacaccttttgtgaac-3′ 22 591 161 Probe TET-5′-acattggcctagccaaatatgcatgt-3′-TAMRA 26 613 162 Reverse 5′-ggaaaacccataccaaatgttt-3′ 22 653 163

[0687] TABLE 52 Probe Name Ag2337 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-attccacacaccttttgtgaac-3′ 22 591 164 Probe TET-5′-acattggcctagccaaatatgcatgt-3′-TAMRA 26 613 165 Reverse 5′-ggaaaacccataccaaatgttt-3′ 22 653 166

[0688] TABLE 53 Panel 4.1D Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag2319, Ag2337, Ag2319, Ag2337, Run Run Run Run Tissue Name 224781588 224781634 Tissue Name 224781588 224781634 Secondary Th1 act 0.0 0.0 HUVEC IL-1beta 0.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN 0.0 0.0 gamma Secondary Tr1 act 0.0 0.0 HUVEC TNF 0.0 0.0 alpha + IFN gamma Secondary Th1 rest 0.0 0.0 HUVEC TNF 0.0 0.0 alpha + IL4 Secondary Th2 rest 0.0 0.0 HUVEC IL-11 0.0 0.0 Secondary Tr1 rest 0.0 0.0 Lung 0.0 0.0 Microvascular EC none Primary Th1 act 0.0 0.0 Lung 0.0 0.0 Microvascular EC TNFalpha + IL- 1beta Primary Th2 act 0.0 0.0 Microvascular 0.0 0.0 Dermal EC none Primary Tr1 act 0.0 0.0 Microsvasular 0.0 0.0 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 0.0 0.0 Bronchial 0.0 0.0 epithelium TNFalpha + IL1beta Primary Th2 rest 0.0 0.0 Small airway 0.0 0.0 epithelium none Primary Tr1 rest 0.0 0.0 Small airway 0.0 0.0 epithelium TNFalpha + IL- 1beta CD45RA CD4 0.0 0.0 Coronery artery 0.0 0.0 lymphocyte act SMC rest CD45RO CD4 0.0 0.0 Coronery artery 0.0 0.0 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 0.0 0.0 Astrocytes rest 0.0 0.0 act Secondary CD8 0.0 0.0 Astrocytes 0.0 0.0 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 0.0 0.0 KU-812 0.0 0.0 lymphocyte act (Basophil) rest CD4 lymphocyte 0.0 0.0 KU-812 0.0 0.0 none (Basophil) PMA/ionomycin 2ry 0.0 0.0 CCD1106 0.0 0.0 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 0.0 CCD1106 0.0 0.0 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 0.0 0.0 Liver cirrhosis 0.0 0.0 LAK cells IL-2 + IL- 0.0 0.0 NCI-H292 none 0.0 0.0 12 LAK cells IL- 0.0 0.0 NCI-H292 IL-4 0.0 0.0 2 + IFN gamma LAK cells IL-2 + 0.0 0.0 NCI-H292 IL-9 0.0 0.0 IL-18 LAK cells 0.0 0.0 NCI-H292 IL-13 0.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 NCI-H292 IFN 0.0 0.0 gamma Two Way MLR 3 0.0 0.0 HPAEC none 0.0 0.0 day Two Way MLR 5 0.0 0.0 HPAEC TNF 0.0 0.0 day alpha + IL-1 beta Two Way MLR 7 0.0 0.0 Lung fibroblast 0.0 0.0 day none PBMC rest 0.0 0.0 Lung fibroblast 0.0 0.0 TNF alpha + IL-1 beta PBMC PWM 0.0 0.0 Lung fibroblast 0.0 0.0 IL-4 PBMC PHA-L 0.0 0.0 Lung fibroblast 0.0 0.0 IL-9 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 none IL-13 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 ionomycin IFN gamma B lymphocytes 0.0 0.0 Dermal fibroblast 0.0 0.0 PWM CCD1070 rest B lymphocytes 0.0 0.0 Dermal fibroblast 0.0 0.0 CD40L and IL-4 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 CCD1070 IL-1 beta EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 1.0 PMA/ionomycin IFN gamma Dendritic cells 0.0 0.0 Dermal fibroblast 0.0 0.0 none IL-4 Dendritic cells LPS 0.0 0.0 Dermal 0.0 0.0 Fibroblasts rest Dendritic cells anti- 0.0 0.0 Neutrophils 0.0 1.2 CD40 TNFa + LPS Monocytes rest 0.0 0.0 Neutrophils rest 0.0 1.1 Monocytes LPS 0.0 0.0 Colon 0.0 0.0 Macrophages rest 0.0 0.0 Lung 1.7 1.8 Macrophages LPS 0.0 0.0 Thymus 9.6 14.5 HUVEC none 0.0 0.0 Kidney 100.0 100.0 HUVEC starved 0.0 0.0

[0689] CNS_neurodegeneration_v1.0 Summary Ag2319/Ag2337 Expression of the GPCR5 gene is low/undetectable (CTs>35) across all of the samples on this panel (data not shown).

[0690] General_screening_panel_v1.5 Summary Ag2337 Expression of the GPCR5 gene is low/undetectable (CTs>35) across all of the samples on this panel due to a probable probe failure. (data not shown).

[0691] Panel 1.3D Summary Ag2319/Ag2337 Expression of the GPCR5 gene is low/undetectable (CTs>35) across all of the samples on this panel due to a probable probe failure. (data not shown).

[0692] Panel 2.2 Summary Ag2319 Expression of the GPCR5 gene is low/undetectable (CTs >35) across all of the samples on this panel due to a probable probe failure. (data not shown-Run 174309682). A suspicious amp plot from a second experiment with the same probe and primer set suggests that there were experimental difficulties with that run. (Data not shown-Run 174310428.)

[0693] Panel 4.1D Summary: Ag2319/Ag2337 Expression of the GPCR5 gene is limited to kidney. Therefore, expression of this gene could be used to distinguish kidney from other tissues. Furthermore, the restriction of expression of the GPCR5 gene to the kidney suggests that the protein encoded by this gene may be involved in the homeostasis of the kidney. Therefore, therapeutic modulation of the expression or function of the GPCR5 gene may be effective in the treatment of diseases of the kidney such as diabetes, autoimmune disease, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, and Lesch-Nyhan syndrome.

[0694] Panel 4D Summary Ag2319/Ag2337 Expression of the GPCR5 gene is low/undetectable (CTs>35) in all of the tissues on this panel (data not shown). (Nouri-Aria et al., Basophil recruitment and IL-4 production during human allergen-induced late asthma. J Allergy Clin Immunol 108(2):205-11, 2001).

[0695] GPCR6

[0696] Expression of the GPCR6 gene (also referred to as CG50149-01) was assessed using the primer-probe sets Ag2364 and Agl725, described in Tables 54 and 55. Results of the RTQ-PCR runs are shown in Table 56. TABLE 54 Probe Name Ag2364 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-caaccagccacagagatagttg-3′ 22 224 167 Probe TET-5′-cttcttgcaggaagccctccagcatt-3′-TAMRA 26 198 168 Reverse 5′-tctctacacctccgacagtgat-3′ 21 171 169

[0697] TABLE 55 Probe Name Ag1725 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-gctcaggtgacaactctcattc-3′ 22 538 170 Probe TET-5′-tgtgttctgcctcactattccttttgga-3′-TAMRA 28 564 171 Reverse 5′-caccacaattctggcataagat-3′ 22 603 172

[0698] TABLE 56 Panel 4D Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag1725, Ag2364, Ag1725, Ag2364, Run Run Run Run Tissue Name 165767161 162361133 Tissue Name 165767161 162361133 Secondary Th1 act 0.0 0.0 HUVEC IL-1beta 0.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN 0.0 0.0 gamma Secondary Tr1 act 0.0 0.0 HUVEC TNF 0.0 0.0 alpha + IFN gamma Secondary Th1 rest 0.0 0.0 HUVEC TNF 0.0 0.0 alpha + IL4 Secondary Th2 rest 0.0 0.0 HUVEC IL-11 0.0 0.0 Secondary Tr1 rest 2.1 0.0 Lung 2.3 0.0 Microvascular EC none Primary Th1 act 0.0 0.0 Lung 0.0 0.0 Microvascular EC TNFalpha + IL- 1beta Primary Th2 act 0.0 0.0 Microvascular 0.0 0.0 Dermal EC none Primary Tr1 act 0.0 0.0 Microsvasular 0.0 0.0 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 0.0 0.0 Bronchial 0.0 0.0 epithelium TNFalpha + IL1beta Primary Th2 rest 0.0 0.0 Small airway 0.0 0.0 epithelium none Primary Tr1 rest 0.0 0.0 Small airway 0.0 0.0 epithelium TNFalpha + IL- 1beta CD45RA CD4 0.0 0.0 Coronery artery 0.0 0.0 lymphocyte act SMC rest CD45RO CD4 0.0 0.0 Coronery artery 0.0 0.0 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 0.0 0.0 Astrocytes rest 0.0 0.0 act Secondary CD8 0.0 0.0 Astrocytes 0.0 0.0 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 0.0 0.0 KU-812 0.0 13.0 lymphocyte act (Basophil) rest CD4 lymphocyte 0.0 0.0 KU-812 3.7 0.0 none (Basophil) PMA/ionomycin 2ry 0.0 0.0 CCD1106 0.0 0.0 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 0.0 CCD1106 3.0 0.0 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 0.0 0.0 Liver cirrhosis 100.0 100.0 LAK cells IL-2 + IL- 0.0 0.0 Lupus kidney 2.0 0.0 12 LAK cells IL- 0.0 0.0 NCI-H292 none 0.0 0.0 2 + IFN gamma LAK cells IL-2 + 0.0 0.0 NCI-H292 IL-4 0.0 0.0 IL-18 LAK cells 0.0 0.0 NCI-H292 IL-9 0.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 NCI-H292 IL-13 0.0 0.0 Two Way MLR 3 0.0 0.0 NCI-H292 IFN 0.0 0.0 day gamma Two Way MLR 5 0.0 0.0 HPAEC none 0.0 0.0 day Two Way MLR 7 0.0 0.0 HPAEC TNF 0.0 0.0 day alpha + IL-1 beta PBMC rest 0.0 0.0 Lung fibroblast 0.0 0.0 none PBMC PWM 0.0 0.0 Lung fibroblast 0.0 0.0 TNF alpha + IL-1 beta PBMC PHA-L 0.0 0.0 Lung fibroblast 0.0 0.0 IL-4 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 none IL-9 Ramos (B cell) 0.0 0.0 Lung fibroblast 0.0 0.0 ionomycin IL-13 B lymphocytes 0.0 0.0 Lung fibroblast 0.0 0.0 PWM IFN gamma B lymphocytes 0.0 0.0 Dermal fibroblast 0.0 0.0 CD40L and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells 0.0 0.0 Dermal fibroblast 0.0 0.0 none IFN gamma Dendritic cells LPS 0.0 0.0 Dermal fibroblast 0.0 12.0 IL-4 Dendritic cells anti- 0.0 0.0 IBD Colitis 2 6.3 20.7 CD40 Monocytes rest 0.0 0.0 IBD Crohn's 2.9 0.0 Monocytes LPS 0.0 0.0 Colon 9.7 0.0 Macrophages rest 0.0 0.0 Lung 0.0 0.0 Macrophages LPS 0.0 0.0 Thymus 0.0 25.3 HUVEC none 0.0 0.0 Kidney 0.0 0.0 HUVEC starved 4.5 0.0

[0699] CNS_neurodegeneration_v1.0 Summary: Ag2364 Expression is low/undetected in all samples in this panel. (Data not shown.)

[0700] Panel 1.3D Summary: Ag2364 Expression is low/undetected in all samples in this panel. (CTs>35)(Data not shown.)

[0701] Panel 4D Summary: Agl725/Ag2364 The GPCR6 transcript is only detected in liver cirrhosis. Furthermore, this transcript is not detected in normal liver in Panel 1.3D, suggesting that this gene expression is unique to liver cirrhosis. This gene encodes a putative GPCR; therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis. In addition, antibodies to this putative GPCR6 could also be used for the diagnosis of liver cirrhosis.

[0702] GPCR7

[0703] Expression of the GPCR7 gene (also referred to as GM_330202597_A_da1) was assessed using the primer-probe set Ag1173, described in Table 57. TABLE 57 Probe Name Ag1173 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-gcgcaatagaatacgtcaattt-3′ 22 527 173 Probe TET-5′-cagctcctaagcctcttagaccccaa-3′-TAMRA 26 564 174 Reverse 5′-aaccatgactccaatctcaatg-3′ 22 599 175

[0704] CNS_neurodegeneration_v1.0 Summary: Ag1173 The amp plot from one experiment with this probe and primer suggests that there were experimental difficulties with this run.

[0705] Panel 1.2 Summary: Ag1173 Expression is low/undetectable in all samples in this panel. (CTs>35). (Data not shown.)

[0706] Panel 4D Summary: Ag1173 Expression is low/undetectable with questionable amp plots for multiple runs with this probe and primer set. (Data not shown.)

[0707] GPCR8

[0708] Expression of the GPCR8 gene(also referred to as AC076959_da2) was assessed using the primer-probe sets Ag2308, Ag1510, Ag4494, and Ag1538, described in Tables 58, 59, 60 and 61. Results of the RTQ-PCR runs are shown in Tables 62, 63, 64 and 65. TABLE 58 Probe Name Ag2308 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-taccgatcatagcacatcatca-3′ 22 591 176 Probe TET-5′-tcagacactctgtaatagcaaacgcca-3′-TAMRA 27 619 177 Reverse 5′-tgctccttgcatacttcagact-3′ 22 656 178

[0709] TABLE 59 Probe Name Ag1510 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-attctcaagaacggaggaagat-3′ 22 141 179 Probe TET-5′-tttacagccttttcaacccgatcctg-3′-TAMRA 26 104 180 Reverse 5′-tctgcattcctaaggctgtaga-3′ 22 72 181

[0710] TABLE 60 Probe Name Ag4494 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-attctcaagaacggaggaagat-3′ 22 141 182 Probe TET-5′-tttacagccttttcaacccgatcctg-3′-TAMRA 26 104 183 Reverse 5′-tctgcattcctaaggctgtaga-3′ 22 72 184

[0711] TABLE 61 Probe Name Ag1538 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-AGGAAGATCCTTTCCCTGTTT-3′ 21 171 185 Probe TET-5′-TACAGCCTTTTCAACCCGATCCTGAA-3′-TAMRA 26 192 186 Reverse 5′-CTCTCTTTAGAGCCCCTTTCAC-3′ 22 249 187

[0712] TABLE 62 CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag2308, Rel. Exp. (%) Ag2308, Tissue Name Run 207970871 Tissue Name Run 207970871 AD 1 Hippo 0.0 Control (Path) 3 0.0 Temporal Ctx AD 2 Hippo 9.8 Control (Path) 4 10.7 Temporal Ctx AD 3 Hippo 0.0 AD 1 Occipital Ctx 24.0 AD 4 Hippo 18.2 AD 2 Occipital Ctx 0.0 (Missing) AD 5 Hippo 16.6 AD 3 Occipital Ctx 0.0 AD 6 Hippo 81.8 AD 4 Occipital Ctx 1.2 Control 2 Hippo 0.0 AD 5 Occipital Ctx 1.8 Control 4 Hippo 38.7 AD 5 Occipital Ctx 1.9 Control (Path) 3 1.2 Control 1 Occipital 17.6 Hippo Ctx AD 1 Temporal Ctx 16.4 Control 2 Occipital 0.0 Ctx AD 2 Temporal Ctx 14.6 Control 3 Occipital 17.2 Ctx AD 3 Temporal Ctx 0.0 Control 4 Occipital 30.8 Ctx AD 4 Temporal Ctx 20.4 Control (Path) 1 0.0 Occipital Ctx AD 5 Inf Temporal 15.1 Control (Path) 2 11.7 Ctx Occipital Ctx AD 5 Sup Temporal 27.9 Control (Path) 3 0.0 Ctx Occipital Ctx AD 6 Inf Temporal 13.0 Control (Path) 4 16.7 Ctx Occipital Ctx AD 6 Sup Temporal 1.6 Control 1 Parietal 0.0 Ctx Ctx Control 1 Temporal 0.0 Control 2 Parietal 0.0 Ctx Ctx Control 2 Temporal 1.2 Control 3 Parietal 0.0 Ctx Ctx Control 3 Temporal 100.0 Control (Path) 1 4.0 Ctx Parietal Ctx Control 3 Temporal 38.7 Control (Path) 2 0.0 Ctx Parietal Ctx Control (Path) 1 16.2 Control (Path) 3 10.3 Temporal Ctx Parietal Ctx Control (Path) 2 0.0 Control (Path) 4 31.0 Temporal Ctx Parietal Ctx

[0713] TABLE 63 General_screening_panel_v1.4 Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag1510, Ag4494, Ag1510, Ag4494, Run Run Run Run Tissue Name 222653849 222666589 Tissue Name 222653849 222666589 Adipose 14.2 6.1 Renal ca. TK-10 8.3 13.8 Melanoma* 9.0 0.0 Bladder 100.0 24.3 Hs688 (A).T Melanoma* 4.2 6.7 Gastric ca. (liver 3.7 9.7 Hs688 (B).T met.) NCI-N87 Melanoma* 0.0 0.0 Gastric ca. 1.7 8.7 M14 KATO III Melanoma* 0.0 0.0 Colon ca. SW- 0.0 0.0 LOXIMVI 948 Melanoma* 0.0 0.0 Colon ca. SW480 0.0 0.0 SK-MEL-5 Squamous cell 0.0 0.0 Colon ca.* 0.0 8.2 carcinoma (SW480 met) SCC-4 SW620 Testis Pool 6.9 0.0 Colon ca. HT29 2.4 0.0 Prostate ca.* 0.0 0.0 Colon ca. HCT- 0.0 12.8 (bone met) 116 PC-3 Prostate Pool 10.6 7.2 Colon ca. CaCo-2 11.0 8.4 Placenta 2.5 2.3 Colon cancer 19.3 10.3 tissue Uterus Pool 4.0 2.5 Colon ca. 0.0 0.0 SW1116 Ovarian ca. 12.5 8.6 Colon ca. Colo-205 0.0 0.0 OVCAR-3 Ovarian ca. 2.2 3.6 Colon ca. SW-48 0.0 0.0 SK-OV-3 Ovarian ca. 0.0 0.0 Colon Pool 3.0 5.5 OVCAR-4 Ovarian ca. 0.0 17.2 Small Intestine 11.0 6.5 OVCAR-5 Pool Ovarian ca. 0.0 0.0 Stomach Pool 21.6 24.8 IGROV-1 Ovarian ca. 5.7 0.0 Bone Marrow 57.4 22.4 OVCAR-8 Pool Ovary 13.5 15.7 Fetal Heart 0.0 0.0 Breast ca. 0.0 3.0 Heart Pool 19.1 7.3 MCF-7 Breast ca. 4.0 2.2 Lymph Node 27.9 29.5 MDA-MB- Pool 231 Breast ca. BT 0.0 0.0 Fetal Skeletal 0.0 0.0 549 Muscle Breast ca. 16.2 2.2 Skeletal Muscle 0.0 0.0 T47D Pool Breast ca. 0.0 7.1 Spleen Pool 4.3 5.4 MDA-N Breast Pool 8.3 0.0 Thymus Pool 7.9 13.1 Trachea 7.1 2.7 CNS cancer 0.0 0.0 (glio/astro) U87- MG Lung 3.4 7.2 CNS cancer 6.7 0.0 (glio/astro) U- 118-MG Fetal Lung 29.9 34.9 CNS cancer 0.0 0.0 (neuro;met) SK- N-AS Lung ca. NCI- 0.0 0.0 CNS cancer 0.0 0.0 N417 (astro) SF-539 Lung ca. LX- 9.2 14.7 CNS cancer 0.0 0.0 1 (astro) SNB-75 Lung ca. NCI- 0.0 0.0 CNS cancer 0.0 0.0 H146 (glio) SNB-19 Lung ca. 0.0 0.0 CNS cancer 0.0 2.8 SHP-77 (glio) SF-295 Lung ca. 0.0 0.0 Brain 0.0 0.0 A549 (Amygdala) Pool Lung ca. NCI- 0.0 0.0 Brain 0.0 0.0 H526 (cerebellum) Lung ca. NCI- 3.4 4.1 Brain (fetal) 0.0 6.5 H23 Lung ca. NCI- 0.0 0.0 Brain 0.0 0.0 H460 (Hippocampus) Pool Lung ca. 3.1 0.0 Cerebral Cortex 0.0 0.0 HOP-62 Pool Lung ca. NCI- 0.0 0.0 Brain (Substantia 0.0 0.0 H522 nigra) Pool Liver 0.0 0.0 Brain (Thalamus) 0.0 8.5 Pool Fetal Liver 6.9 9.9 Brain (whole) 0.0 0.0 Liver ca. 8.8 14.1 Spinal Cord Pool 0.0 9.7 HepG2 Kidney Pool 19.2 4.5 Adrenal Gland 3.7 3.9 Fetal Kidney 70.7 100.0 Pituitary gland 0.0 3.5 Pool Renal ca. 786- 34.6 32.8 Salivary Gland 3.2 0.0 0 Renal ca. 16.2 5.9 Thyroid (female) 3.2 3.1 A498 Renal ca. 3.4 2.8 Pancreatic ca. 2.4 0.0 ACHN CAPAN2 Renal ca. UO- 1.9 2.6 Pancreas Pool 17.9 18.3 31

[0714] TABLE 64 Panel 1.2 Rel. Exp. (%) Ag1510, Rel. Exp. (%) Ag1510, Tissue Name Run 141938638 Tissue Name Run 141938638 Endothelial cells 0.0 Renal ca. 786-0 11.9 Heart (Fetal) 0.0 Renal ca. A498 24.3 Pancreas 0.6 Renal ca. RXF 393 22.2 Pancreatic ca. 0.3 Renal ca. ACHN 2.6 CAPAN 2 Adrenal Gland 2.7 Renal ca. UO-31 43.8 Thyroid 1.0 Renal ca. TK-10 8.2 Salivary gland 49.7 Liver 11.2 Pituitary gland 0.0 Liver (fetal) 3.1 Brain (fetal) 0.0 Liver ca. 55.1 (hepatoblast) HepG2 Brain (whole) 0.0 Lung 0.0 Brain (amygdala) 0.0 Lung (fetal) 0.0 Brain (cerebellum) 0.0 Lung ca. (small cell) 4.6 LX-1 Brain (hippocampus) 0.0 Lung ca. (small cell) 61.1 NCI-H69 Brain (thalamus) 0.0 Lung ca. (s. cell var.) 0.0 SHP-77 Cerebral Cortex 0.0 Lung ca. (large 46.7 cell) NCI-H460 Spinal cord 0.0 Lung ca. (non-sm. 23.0 cell) A549 glio/astro U87-MG 0.0 Lung ca. (non-s. cell) 6.1 NCI-H23 glio/astro U-118-MG 2.3 Lung ca. (non-s. cell) 51.1 HOP-62 astrocytoma SW1783 14.7 Lung ca. (non-s. cl) 0.0 NCI-H522 neuro*; met SK-N-AS 0.0 Lung ca. (squam.) 37.9 SW 900 astrocytoma SF-539 4.5 Lung ca. (squam.) 27.7 NCI-H596 astrocytoma SNB-75 0.0 Mammary gland 15.4 glioma SNB-19 13.8 Breast ca.* (pl. ef) 2.5 MCF-7 glioma U251 0.0 Breast ca.* (pl. ef) 0.0 MDA-MB-231 glioma SF-295 7.3 Breast ca.* (pl. ef) 1.8 T47D Heart 2.8 Breast ca. BT-549 6.4 Skeletal Muscle 0.0 Breast ca. MDA-N 19.9 Bone marrow 2.9 Ovary 1.7 Thymus 0.0 Ovarian ca. OVCAR-3 6.8 Spleen 0.0 Ovarian ca. OVCAR-4 11.8 Lymph node 1.3 Ovarian ca. OVCAR-5 100.0 Colorectal 14.0 Ovarian ca. OVCAR-8 42.3 Stomach 3.6 Ovarian ca. IGROV-1 0.0 Small intestine 0.3 Ovarian ca. (ascites) 0.0 SK-OV-3 Colon ca. SW480 0.0 Uterus 0.3 Colon ca.* SW620 0.6 Placenta 3.8 (SW480 met) Colon ca. HT29 27.0 Prostate 12.1 Colon ca. HCT-116 7.2 Prostate ca.* (bone 6.3 met) PC-3 Colon ca. CaCo-2 0.0 Testis 7.1 CC Well to Mod Diff 30.8 Melanoma 11.9 (ODO3866) Hs688 (A).T Colon ca. HCC-2998 27.5 Melanoma* (met) 27.5 Hs688 (B).T Gastric ca. (liver met) 12.6 Melanoma UACC-62 0.0 NCI-N87 Bladder 83.5 Melanoma M14 67.4 Trachea 0.0 Melanoma LOX 0.0 IMVI Kidney 100.0 Melanoma* (met) 0.0 SK-MEL-5 Kidney (fetal) 14.2

[0715] TABLE 65 Panel 4D Rel. Exp. (%) Ag2308, Rel. Exp. (%) Ag2308, Tissue Name Run 158927487 Tissue Name Run 158927487 Secondary Th1 act 0.0 HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 17.4 Secondary Tr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 17.2 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 4.4 Secondary Tr1 rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 11.3 Lung Microvascular EC 0.0 TNFalpha + IL-1beta Primary Th2 act 0.0 Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 24.0 Bronchial epithelium 0.0 TNFalpha + IL1beta Primary Th2 rest 14.5 Small airway epithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 15.1 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyte act CD45RO CD4 6.0 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 0.0 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.0 KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812 (Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106 (Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 Liver cirrhosis 29.1 LAK cells IL-2 + IL-12 0.0 Lupus kidney 9.9 LAK cells IL-2 + IFN 21.8 NCI-H292 none 26.6 gamma LAK cells IL-2 + IL-18 0.0 NCI-H292 IL-4 28.7 LAK cells 0.0 NCI-H292 IL-9 37.9 PMA/ionomycin NK Cells IL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 10.6 NCI-H292 IFN gamma 13.3 Two Way MLR 5 day 21.5 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 11.3 PBMC PWM 0.0 Lung fibroblast TNF alpha + 0.0 IL-1 beta PBMC PHA-L 14.6 Lung fibroblast IL-4 18.6 Ramos (B cell) none 0.0 Lung fibroblast IL-9 0.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 15.9 ionomycin B lymphocytes PWM 0.0 Lung fibroblast IFN 22.2 gamma B lymphocytes CD40L 0.0 Dermal fibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast 6.7 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermal fibroblast IFN 0.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-4 27.5 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 0.0 IBD Crohn's 0.0 Monocytes LPS 0.0 Colon 8.7 Macrophages rest 7.5 Lung 47.0 Macrophages LPS 0.0 Thymus 100.0 HUVEC none 0.0 Kidney 5.8 HUVEC starved 0.0

[0716] CNS_neurodegeneration_v1.0 Summary: Ag2308 Highest expression of the GPCR8 gene is detected in the temporal cortex of a control patient (CT=33.34) with expression also detected in the hippocampus in both a control brain and a brain from a patient with Alzheimer's disease. The GPCR8 gene encodes a putative GPCR. Several neurotransmitter receptors are GPCrs, including the dopamine receptor family, the serotonin receptor family, the GABAB receptor, muscarinic acetylcholine receptors, and others; thus the GPCR8 gene product may represent a novel neurotransmitter receptor. Targeting various neurotransmitter receptors (dopamine, serotonin) has proven to be an effective therapy in psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. Furthermore, the cerebral cortex and hippocampus are regions of the brain that are known to be involved in Alzheimer's disease, seizure disorders, and in the normal process of memory formation. Therefore, therapeutic modulation of the GPCR8 gene or its protein product may be beneficial in the treatment of one or more of these diseases, as may stimulation and/or blockade of the receptor coded for by the GPCR8 gene.

[0717] Ag1510/Ag4494 (identical sequence) Please note that two experiments with a second probe and primer set showed low/undetectable levels of expression across all samples in this panel. (CT>35). (Data not shown.)

[0718] General_screening_panel_v1.4 Summary: Ag1510/Ag4494 (identical sequence) two runs with same probe and primer set produce results that are in good agreement with highest expression in the bladder and fetal kidney (CTs=32.5-33.5). Of note is the difference in expression between the fetal kidney (CTs=32.5-34) and the adult kidney (CTs=36-37). Thus, expression of the GPCR8 gene could be used to differentiate between adult and fetal kidney tissue.

[0719] Panel 1.2 Summary: Ag1510 Moderate expression of the the GPCR8 gene is detected in both adult kidney tissue and ovarian cancer cell lines (CTs=31.4). This result suggests that therapeutic modulation of the transcript of the GPCR8 gene may be effective in the treatment of ovarian cancer. Furthermore, the overexpression of this gene in adult kidney as compared to the lower expression level in fetal kidney (CT=34.3) indicates that this gene could be used to differentiate between adult and fetal kidney tissue. The GPCR8 gene is expressed at low levels in a wide variety of both healthy tissues and cancerous cell lines. Cancerous cell lines demonstrating expression of the gene include lung, kidney, colon and other ovarian cancer cell lines. Thus, expression of the GPCR8 gene could potentially be used to distinguish cancer cells from their normal counterparts. Therefore, therapeutic modulation of the protein product of the gene may be of utility in the treatment of lung, kidney or colon cancer. Healthy tissues demonstrating significant expression of gene include bladder and salivary gland tissue. Ag1538 Expression of the gene is low/undetectable (CT values>35) across all of the samples on this panel (data not shown).

[0720] Panel 1.3D Summary Ag2308 Expression is low/undet. (CT>35) in all samples shown in this Panel. (Data not shown.)

[0721] Panel 4.1D Summary Ag1510/Ag4494 (identical sequence) Expression is low/undet. (CT>35) in all samples in this panel. (Data not shown.)

[0722] Panel 4D Summary: Ag1538/Ag2308 Expression of the GPCR8 gene is detected in the thymus (CT=33.3) and lung (CT=34.4) using the probe/primer set Ag2308. This observation suggests that the GPCR8 gene could be used as a marker to detect the presence of thymus or lung tissue. The putative GPCR encoded for by the GPCR8 gene may also play an important role in the normal homeostasis of these tissues. Therapeutics designed with the GPCR8 protein product could be important for maintaining or restoring normal function to these organs during inflammation. Ag1538 Expression of the gene is low/undetectable (CT values>35) across all of the samples on this panel (data not shown).

[0723] GPCR9

[0724] Expression of GPCR9 gene (also referred to as AC073364_da1) was assessed using the primer-probe set Ag2310, described in Table 66. Results of the RTQ-PCR runs are shown in Table 67. TABLE 66 Probe Name Ag2310 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-catgctgtgaccatcatcatta-3′ 22 619 188 Probe TET-5′-ccttcctaatcattgccctgtcctatg-3′-TAMRA 27 641 189 Reverse 5′-cttcagaagagggaatcctcaa-3′ 22 688 190

[0725] TABLE 67 Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2310, Run Ag2310, Run Tissue Name 162308429 Tissue Name 162308429 Secondary Th1 act 0.0 HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Tr1 act 16.8 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1 rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 Lung Microvascular EC 0.0 TNFalpha + IL-1beta Primary Th2 act 0.0 Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 0.0 Bronchial epithelium 2.5 TNFalpha + IL1beta Primary Th2 rest 0.0 Small airway epithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyte act CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 0.0 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.0 KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812 (Basophil) 24.3 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106 (Keratinocytes) 14.3 CD95 CH11 none LAK cells rest 0.0 CCD1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 Liver cirrhosis 10.8 LAK cells IL-2 + IL-12 0.0 Lupus kidney 0.0 LAK cells IL-2 + IFN 0.0 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 0.0 NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCI-H292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0 PBMC PWM 0.0 Lung fibroblast TNF alpha + 0.0 IL-1 beta PBMC PHA-L 0.0 Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-9 0.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 0.0 ionomycin B lymphocytes PWM 15.7 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 0.0 Dermal fibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermal fibroblast IFN 0.0 gamma Dendritic cells LPS 2.8 Dermal fibroblast IL-4 0.0 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 0.0 IBD Crohn's 0.0 Monocytes LPS 20.3 Colon 0.0 Macrophages rest 100.0 Lung 3.9 Macrophages LPS 0.0 Thymus 11.2 HUVEC none 0.0 Kidney 12.0 HUVEC starved 0.0

[0726] Panel 1.3D Summary Ag2310 Expression low/undetectable (CT values>34.5) across the samples on this panel.

[0727] Panel 2.2 Summary Ag2310 Expression low/undetectable (CT values>34.5) across the samples on this panel.

[0728] Panel 4.1D Summary Ag3210 Expression low/undetectable (CT values>34.5) across the samples on this panel.

[0729] Panel 4D Summary: Ag2310 Teh GPCR9 transcript is detected at significant levels in resting macrophates. The putative GPCR encoded for by this gene is down regulated in macrophages after LPS stimulation. Therefore, the GPCR9 gene may function to respond to inflammatory stimuli and become down regulated after 12-24 hr exposure. Antibody or small molecule therapeutics designe againts this putative GPCR could thus reduce or inhibit inflammation and be important in diseases such as asthma, IBD, psoriasis, arthritis and allergy Furthermore, agonistic (lingand-like) therapeutics designed with the putative GPCR could “jump start” the immune response and improve the efficacy of vaccines and antiviral or antibacterial treatments.

[0730] GPCR10

[0731] Expression of GPCR10 gene(also refered to as CG55732

[0732] -01) was assessed using the primer-probe set Ag2588, described in Table 68. Results of the RTQ-PCR runs are shown in Table 69. TABLE 68 Probe Name Ag2588 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-gaagaggatctgtatggttgca-3′ 22 532 191 Probe TET-5′-tcctacccatgacactcccactagca-3′-TAMRA 26 565 192 Reverse 5′-tgcactataccaccatcatgaa-3′ 22 608 193

[0733] TABLE 69 Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2588, Run Ag2588, Run Tissue Name 164327719 Tissue Name 164327719 Secondary Th1 act 0.0 HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Tr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 13.7 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 2.5 Secondary Tr1 rest 13.7 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 Lung Microvascular EC 5.5 TNFalpha + IL-1beta Primary Th2 act 0.0 Microvascular Dermal EC 3.7 none Primary Tr1 act 0.0 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 0.0 Bronchial epithelium 0.0 TNFalpha + IL1beta Primary Th2 rest 0.0 Small airway epithelium 16.8 none Primary Tr1 rest 0.0 Small airway epithelium 17.4 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyte act CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 6.2 Secondary CD8 0.0 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.0 KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812 (Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 4.4 CCD1106 (Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 Liver cirrhosis 100.0 LAK cells IL-2 + IL-12 13.3 Lupus kidney 0.0 LAK cells IL-2 + IFN 0.0 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 0.0 NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 11.0 PMA/ionomycin NK Cells IL-2 rest 0.0 NCI-H292 IL-13 6.6 Two Way MLR 3 day 0.0 NCI-H292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0 PBMC PWM 0.0 Lung fibroblast TNF alpha + 0.0 IL-1 beta PBMC PHA-L 0.0 Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-9 0.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 0.0 ionomycin B lymphocytes PWM 0.0 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 0.0 Dermal fibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast 9.3 CCD1070 TNF alpha EOL-1 dbcAMP 2.6 Dermal fibroblast 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermal fibroblast IFN 6.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-4 17.7 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 0.0 IBD Crohn's 7.7 Monocytes LPS 0.0 Colon 0.0 Macrophages rest 0.0 Lung 0.0 Macrophages LPS 0.0 Thymus 0.0 HUVEC none 0.0 Kidney 0.0 HUVEC starved 0.0

[0734] CNS_neurodegeneration_v1.0 Summary: Ag2588 Expression is low/undetected in all samples in this panel (CTh35). (Data not shown.)

[0735] Panel 1.3D Summary: Ag2588 Expression is low/undetected in all samples in this panel (CT>35). (Data not shown.)

[0736] Panel 4D Summary: Ag2588 The GPCR10 transcript is only detected in liver cirrhosis. Furthermore, this transcript is not detected in normal liver in Panel 1.3D, suggesting that this gene expression is unique to liver cirrhosis. The GPCR10 gene encodes a putative GPCR; therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis. In addition, antibodies to this putative GPCR could also be used for the diagnosis of liver cirrhosis.

[0737] GPCR11

[0738] Expression of the GPCR11 gene (also referred to as sggc_draft_ba656o22_20000731_da1) was assessed using the primer-probe set Ag1898, described in Table 70. Results of the RTQ-PCR runs are shown in Table 71. TABLE 70 Probe Name Ag1898 SEQ ID Primers Sequences Length Start Position NO: Forward 5′-ggctgtggtgtctctgttttac-3′ 122 740 194 Probe TET-5′-catcttcatgtatctccagccagcca-3′-TAMRA 26 770 195 Reverse 5′-ctatgaacttgccctgctcat-3′ 21 808 196

[0739] TABLE 71 Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Ag1898, Run Ag1898, Run Tissue Name 165544705 Tissue Name 165544705 Liver adenocarcinoma 0.0 Kidney (fetal) 0.0 Pancreas 0.0 Renal ca. 786-0 0.0 Pancreatic ca. 0.0 Renal ca. A498 0.0 CAPAN 2 Adrenal gland 0.0 Renal ca. RXF 393 0.0 Thyroid 0.0 Renal ca. ACHN 0.0 Salivary gland 0.0 Renal ca. UO-31 0.0 Pituitary gland 0.0 Renal ca. TK-10 0.0 Brain (fetal) 0.0 Liver 0.0 Brain (whole) 1.7 Liver (fetal) 0.0 Brain (amygdala) 0.0 Liver ca. 0.0 (hepatoblast) HepG2 Brain (cerebellum) 29.9 Lung 0.0 Brain (hippocampus) 0.0 Lung (fetal) 0.0 Brain (substantia nigra) 1.2 Lung ca. (small cell) 0.0 LX-1 Brain (thalamus) 0.0 Lung ca. (small cell) 0.0 NCI-H69 Cerebral Cortex 0.0 Lung ca. (s. cell var.) 0.3 SHP-77 Spinal cord 0.0 Lung ca. (large 0.0 cell) NCI-H460 glio/astro U87-MG 0.0 Lung ca. (non-sm. 0.0 cell) A549 glio/astro U-118-MG 0.0 Lung ca. (non-s. cell) 0.0 NCI-H23 astrocytoma SW1783 0.0 Lung ca. (non-s. cell) 0.0 HOP-62 neuro*; met SK-N-AS 0.0 Lung ca. (non-s. cl) 0.0 NCI-H522 astrocytoma SF-539 2.6 Lung ca. (squam.) SW 900 0.0 astrocytoma SNB-75 0.0 Lung ca. (squam.) 0.0 NCI-H596 glioma SNB-19 0.0 Mammary gland 0.0 glioma U251 0.0 Breast ca.* (pl. ef) 0.0 MCF-7 glioma SF-295 0.0 Breast ca.* (pl. ef) 0.0 MDA-MB-231 Heart (Fetal) 0.0 Breast ca.* (pl. ef) 0.0 T47D Heart 0.0 Breast ca. BT-549 0.0 Skeletal muscle (Fetal) 0.0 Breast ca. MDA-N 4.1 Skeletal muscle 0.0 Ovary 0.8 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0 Thymus 1.3 Ovarian ca. OVCAR-4 0.0 Spleen 0.0 Ovarian ca. OVCAR-5 0.0 Lymph node 2.2 Ovarian ca. OVCAR-8 0.0 Colorectal 0.0 Ovarian ca. IGROV-1 0.0 Stomach 0.0 Ovarian ca. (ascites) 0.0 SK-OV-3 Small intestine 0.0 Uterus 0.0 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* SW620 0.0 Prostate 4.2 (SW480 met) Colon ca. HT29 0.0 Prostate ca.* (bone 0.0 met) PC-3 Colon ca. HCT-116 0.0 Testis 31.9 Colon ca. CaCo-2 0.0 Melanoma 0.0 Hs688(A).T CC Well to Mod Diff 0.0 Melanoma* (met) 0.0 (ODO3866) Hs688(B).T Colon ca. HCC-2998 0.0 Melanoma UACC-62 2.3 Gastric ca. (liver met) 0.0 Melanoma M14 6.0 NCI-N87 Bladder 0.0 Melanoma LOX 0.0 IMVI Trachea 0.0 Melanoma* (met) 100.0 SK-MEL-5 Kidney 0.0 Adipose 0.0

[0740] Panel 1.3D Summary: Ag1898 Highest expression of the GPCR11 gene is detected in a melanoma cell line (CT=31) with low but significant expression also seen in the cerebellum and testis. Thus, the expression of this gene could be used to distinguish samples derived from this melanoma cell line from other samples. In addition, therapeutic modulation of the expression or function of the GPCR11 gene, through the use of small molecule drugs or antibodies, might be of use in the treatment of melanoma.

[0741] The GPCR11 gene is also expressed differentially in the cerebellum. Cerebellar G protein function is known to be defective in Alzheimer's disease cerebella, suggesting this cerebellum-preferential GPCR may have utility as a drug target to counter the G-protein signaling deficit in Alzheimer's disease (Fowler et al., Receptor-effector coupling dysfunctions in Alzheimer's disease. Ann N Y Acad Sci. 786:294-304, 1996; Cowburn et al., Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer's disease. J Neurochem. 58:1409-19, 1992).

[0742] Panel 4D Summary: Ag1898 Expression of this gene is low/undetectable (Ct values >35) in all samples on this panel (data not shown).

[0743] GPCR12

[0744] Expression of the GPCR12 gene (also referred to as ba407h12_da1) was assessed using the primer-probe set Ag1726, described in Table 72. Results of the RTQ-PCR runs are shown in Tables 73 and 74. TABLE 72 Probe Name Ag1726 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-acctcccaacaaccttctgtag-3′ 22 903 197 Probe 5′-ccgtgacatccttgttcctaaggctg-3′-TAMRA 26 872 198 Reverse 5′-ccatgctcaatccactcattta-3′ 22 850 199

[0745] TABLE 73 Panel 2.2 Rel. Exp. (%) Rel. Exp. (%) Ag1726, Run Ag1726, Run Tissue Name 173761836 Tissue Name 173761836 Normal Colon 0.0 Kidney Margin 20.3 (OD04348) Colon cancer 0.0 Kidney malignant 3.1 (OD06064) cancer (OD06204B) Colon Margin 0.0 Kidney normal adjacent 0.0 (OD06064) tissue (OD06204E) Colon cancer 0.0 Kidney Cancer 4.0 (OD06159) (OD04450-01) Colon Margin 3.3 Kidney Margin 0.0 (OD06159) (OD04450-03) Colon cancer 0.0 Kidney Cancer 8120613 0.0 (OD06297-04) Colon Margin 0.0 Kidney Margin 2.6 (OD06297-015) 8120614 CC Gr.2 ascend colon 0.0 Kidney Cancer 9010320 0.0 (ODO3921) CC Margin (ODO3921) 0.0 Kidney Margin 0.0 9010321 Colon cancer metastasis 0.0 Kidney Cancer 8120607 0.0 (OD06104) Lung Margin 0.0 Kidney Margin 0.0 (OD06104) 8120608 Colon mets to lung 0.0 Normal Uterus 0.0 (OD04451-01) Lung Margin 0.0 Uterine Cancer 064011 0.0 (OD04451-02) Normal Prostate 0.0 Normal Thyroid 0.0 Prostate Cancer 0.0 Thyroid Cancer 0.0 (OD04410) Prostate Margin 0.0 Thyroid Cancer 0.0 (OD04410) A302152 Normal Ovary 0.0 Thyroid Margin 0.0 A302153 Ovarian cancer 0.0 Normal Breast 0.0 (OD06283-03) Ovarian Margin 0.0 Breast Cancer 3.3 (OD06283-07) Ovarian Cancer 100.0 Breast Cancer 0.0 Ovarian cancer 0.0 Breast Cancer 0.0 (OD06145) (OD04590-01) Ovarian Margin 0.0 Breast Cancer Mets 0.0 (OD06145) (OD04590-03) Ovarian cancer 0.0 Breast Cancer 0.0 (OD06455-03) Metastasis Ovarian Margin 0.0 Breast Cancer 0.0 (OD06455-07) Normal Lung 0.0 Breast Cancer 9100266 0.0 Invasive poor diff. lung 0.0 Breast Margin 9100265 0.0 adeno (ODO4945-01 Lung Margin 0.0 Breast Cancer A209073 0.0 (ODO4945-03) Lung Malignant Cancer 0.0 Breast Margin 0.0 (OD03126) A2090734 Lung Margin 0.0 Breast cancer 0.0 (OD03126) (OD06083) Lung Cancer 0.0 Breast cancer node 0.0 (OD05014A) metastasis (OD06083) Lung Margin 0.0 Normal Liver 0.0 (OD05014B) Lung cancer (OD06081) 0.0 Liver Cancer 1026 0.0 Lung Margin 0.0 Liver Cancer 1025 11.3 (OD06081) Lung Cancer 0.0 Liver Cancer 6004-T 0.0 (OD04237-01) Lung Margin 0.0 Liver Tissue 6004-N 0.0 (OD04237-02) Ocular Mel Met to Liver 0.0 Liver Cancer 6005-T 0.0 (ODO4310) Liver Margin 0.0 Liver Tissue 6005-N 0.0 (ODO4310) Melanoma Metastasis 0.0 Liver Cancer 0.0 Lung Margin 0.0 Normal Bladder 0.0 (OD04321) Normal Kidney 0.0 Bladder Cancer 0.0 Kidney Ca, Nuclear 0.0 Bladder Cancer 0.0 grade 2 (OD04338) Kidney Margin 0.7 Normal Stomach 0.0 (OD04338) Kidney Ca Nuclear 0.0 Gastric Cancer 9060397 0.0 grade ½ (OD04339) Kidney Margin 4.3 Stomach Margin 12.9 (OD04339) 9060396 Kidney Ca, Clear cell 0.0 Gastric Cancer 9060395 13.3 type (OD04340) Kidney Margin 0.0 Stomach Margin 0.0 (OD04340) 9060394 Kidney Ca, Nuclear 0.0 Gastric Cancer 064005 0.0 grade 3 (OD04348)

[0746] TABLE 74 Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag1726, Run Ag1726, Run Tissue Name 165364124 Tissue Name 165364124 Secondary Th1 act 0.0 HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Tr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1 rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 Lung Microvascular EC 0.0 TNFalpha + IL-1beta Primary Th2 act 0.0 Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 0.0 Bronchial epithelium 0.0 TNFalpha + IL1beta Primary Th2 rest 7.2 Small airway epithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyte act CD45RO CD4 6.0 Coronery artery SMC 0.0 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 0.0 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.0 KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812 (Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 6.7 CCD1106 (Keratinocytes) 7.0 CD95 CH11 none LAK cells rest 0.0 CCD1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 4.7 Liver cirrhosis 100.0 LAK cells IL-2 + IL-12 0.0 Lupus kidney 5.4 LAK cells IL-2 + IFN 7.1 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 12.7 NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 0.0 PMA/ionomycin NK Cells IL-2 rest 3.8 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCI-H292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 2.4 HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0 PBMC PWM 10.3 Lung fibroblast TNF alpha + 0.0 IL-1 beta PBMC PHA-L 0.0 Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-9 0.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 0.0 ionomycin B lymphocytes PWM 6.4 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 31.2 Dermal fibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermal fibroblast IFN 0.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-4 3.3 Dendritic cells anti- 6.1 IBD Colitis 2 5.3 CD40 Monocytes rest 0.0 IBD Crohn's 7.8 Monocytes LPS 0.0 Colon 6.7 Macrophages rest 0.0 Lung 0.0 Macrophages LPS 0.0 Thymus 19.6 HUVEC none 0.0 Kidney 0.0 HUVEC starved 0.0

[0747] Panel 1.3D Summary Ag1726 Expression of the GPCR12 gene is low/undetectable (CT values>35) across all of the samples on this panel (data not shown).

[0748] Panel 2.2 Summary: Ag1726 The GPCR12 gene is expressed at moderate levels in a sample derived from ovarian cancer (CT=31.4). Thus, expression of this gene could be used to distinguish ovarian cancer from other tissues. In addition, low level of gene expression is observed in a tissue sample from a normal kidney.

[0749] Panel 4D Summary: Summary Ag1726 Expression of the GPCR12 gene is detected at low levels (CT=33.3) in liver cirrhosis, but not in normal liver (no expression in normal liver is detected on Panel 1.3D). The putative GPCR encoded for by this gene could potentially allow cells within the liver to respond to specific microenvironmental signals. Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which effect the liver including liver cirrhosis and fibrosis.

[0750] References

[0751] 1. Mark M D, Wittemann S, Herlitze S (2000) G protein modulation of recombinant P/Q-type calcium channels by regulators of G protein signalling proteins. J Physiol. 528 Pt 1:65-77.

[0752] Fast synaptic transmission is triggered by the activation of presynaptic Ca2+channels which can be inhibited by Gbetagamma subunits via G protein-coupled receptors (GPCR).

[0753] Regulators of G protein signalling (RGS) proteins are GTPase-accelerating proteins (GAPs), which are responsible for>100-fold increases in the GTPase activity of G proteins and might be involved in the regulation of presynaptic Ca2+ channels. In this study we investigated the effects of RGS2 on G protein modulation of recombinant P/Q-type channels expressed in a human embryonic kidney (HEK293) cell line using whole-cell recordings. 2. RGS2 markedly accelerates transmitter-mediated inhibition and recovery from inhibition of Ba2+ currents (IBa) through P/Q-type channels heterologously expressed with the muscarinic acetylcholine receptor M2 (mAChR M2). 3. Both RGS2 and RGS4 modulate the prepulse facilitation properties of P/Q-type Ca2+ channels. G protein reinhibition is accelerated, while release from inhibition is slowed. These kinetics depend on the availability of G protein alpha and betagamma subunits which is altered by RGS proteins. 4. RGS proteins unmask the Ca2+ channel beta subunit modulation of Ca2+ channel G protein inhibition. In the presence of RGS2, P/Q-type channels containing the beta2a and beta3 subunits reveal significantly altered kinetics of G protein modulation and increased facilitation compared to Ca2+channels coexpressed with the beta1b or beta4 subunit. PMID: 11018106

[0754] GPCR13

[0755] Expression of the GPCR13 gene (also referred to as AC074365_da1) was assessed using the primer-probe sets Ag1478 and Ag2501, described in Tables 75 and 76. Results of the RTQ-PCR runs are shown in Tables 77, 78 and 79. TABLE 75 Probe Name Ag1478 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-ctattttggggaataccaccat-3′ 22 181 200 Probe TET-5′-tctcgtctggaacccaagcctcatat-3′-TAMRA 26 213 201 Reverse 5′-ggaaggagagatgagaaaggaa-3′ 22 252 202

[0756] TABLE 76 Probe Name Ag2501 Start SEQ ID Primers Sequences Length Position NO: Forward 5′-acgcagtgttgaggattaagtc-3′ 22 736 203 Probe TET-5′-acagaaagcattcgggacctgcttct-3′-TAMRA 26 770 204 Reverse 5′-tgatggttccataaaagatggt-3′ 22 813 205

[0757] TABLE 77 Panel 1.2 Rel. Exp. (%) Rel. Exp. (%) Ag1478, Run Ag1478, Run Tissue Name 139460019 Tissue Name 139460019 Endothelial cells 0.0 Renal ca. 786-0 0.0 Heart (Fetal) 0.0 Renal ca. A498 9.4 Pancreas 0.0 Renal ca. RXF 393 0.0 Pancreatic ca. 0.0 Renal ca. ACHN 8.8 CAPAN 2 Adrenal Gland 0.0 Renal ca. UO-31 7.0 Thyroid 0.0 Renal ca. TK-10 5.6 Salivary gland 3.6 Liver 0.0 Pituitary gland 0.0 Liver (fetal) 0.0 Brain (fetal) 0.0 Liver ca. 0.0 (hepatoblast) HepG2 Brain (whole) 2.5 Lung 0.0 Brain (amygdala) 0.0 Lung (fetal) 0.0 Brain (cerebellum) 10.9 Lung ca. (small cell) 0.0 LX-1 Brain (hippocampus) 0.0 Lung ca. (small cell) 100.0 NCI-H69 Brain (thalamus) 0.0 Lung ca. (s. cell var.) 1.3 SHP-77 Cerebral Cortex 0.0 Lung ca. (large 24.5 cell) NCI-H460 Spinal cord 0.0 Lung ca. (non-sm. 22.7 cell) A549 glio/astro U87-MG 3.2 Lung ca. (non-s. cell) 3.1 NCI-H23 glio/astro U-118-MG 3.8 Lung ca. (non-s. cell) 40.9 HOP-62 astrocytoma SW1783 0.0 Lung ca. (non-s. cl) 4.1 NCI-H522 neuro*; met SK-N-AS 11.0 Lung ca. (squam.) 5.5 SW 900 astrocytoma SF-539 6.0 Lung ca. (squam.) 24.7 NCI-H596 astrocytoma SNB-75 2.1 Mammary gland 0.0 glioma SNB-19 24.8 Breast ca.* (pl. ef) 0.0 MCF-7 Glioma U251 0.0 Breast ca.* (pl. ef) 0.0 MDA-MB-231 glioma SF-295 1.6 Breast ca.* (pl. ef) 36.1 T47D Heart 2.0 Breast ca. BT-549 8.8 Skeletal Muscle 2.7 Breast ca. MDA-N 12.2 Bone marrow 4.8 Ovary 0.0 Thymus 0.0 Ovarian ca. OVCAR-3 2.7 Spleen 0.0 Ovarian ca. OVCAR-4 0.0 Lymph node 0.0 Ovarian ca. OVCAR-5 59.9 Colorectal 21.9 Ovarian ca. OVCAR-8 9.5 Stomach 0.0 Ovarian ca. IGROV-1 17.9 Small intestine 10.2 Ovarian ca. (ascites) 13.3 SK-OV-3 Colon ca. SW480 0.0 Uterus 0.0 Colon ca.* SW620 0.0 Placenta 0.0 (SW480 met) Colon ca. HT29 8.1 Prostate 16.3 Colon ca. HCT-116 0.0 Prostate ca.* (bone 9.0 met) PC-3 Colon ca. CaCo-2 0.0 Testis 14.2 CC Well to Mod Diff 24.0 Melanoma 5.4 (ODO3866) Hs688(A).T Colon ca. HCC-2998 4.2 Melanoma* (met) 17.0 Hs688(B).T Gastric ca. (liver met) 1.7 Melanoma UACC-62 0.0 NCI-N87 Bladder 8.6 Melanoma M14 61.6 Trachea 0.0 Melanoma LOX 0.0 IMVI Kidney 0.0 Melanoma* (met) 14.4 SK-MEL-5 Kidney (fetal) 0.0

[0758] TABLE 78D Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag1478, Run Ag1478, Run Tissue Name 146936352 Tissue Name 146936352 Normal Colon 0.2 Kidney Margin 0.0 8120608 CC Well to Mod Diff 0.0 Kidney Cancer 0.0 (ODO3866) 8120613 CC Margin (ODO3866) 0.2 Kidney Margin 0.0 8120614 CC Gr.2 rectosigmoid 0.0 Kidney Cancer 0.1 (ODO3868) 9010320 CC Margin (ODO3868) 0.0 Kidney Margin 0.0 9010321 CC Mod Diff (ODO3920) 0.0 Normal Uterus 0.0 CC Margin (ODO3920) 0.0 Uterine Cancer 0.0 064011 CC Gr.2 ascend colon 0.2 Normal Thyroid 0.0 (ODO3921) CC Margin (ODO3921) 0.0 Thyroid Cancer 0.0 CC from Partial 0.0 Thyroid Cancer 0.0 Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.0 Thyroid Margin 0.0 A302153 Colon mets to lung 0.0 Normal Breast 0.0 (OD04451-01) Lung Margin 0.0 Breast Cancer 0.0 (OD04451-02) Normal Prostate 6546-1 0.0 Breast Cancer 0.0 (OD04590-01) Prostate Cancer 0.1 Breast Cancer Mets 0.0 (OD04410) (OD04590-03) Prostate Margin 0.2 Breast Cancer 0.0 (OD04410) Metastasis Prostate Cancer 0.1 Breast Cancer 0.0 (OD04720-01) Prostate Margin 100.0 Breast Cancer 0.0 (OD04720-02) Normal Lung 0.1 Breast Cancer 0.1 9100266 Lung Met to Muscle 0.3 Breast Margin 0.0 (ODO4286) 9100265 Muscle Margin 0.0 Breast Cancer 0.2 (ODO4286) A209073 Lung Malignant Cancer 0.0 Breast Margin 0.0 (OD03126) A2090734 Lung Margin (OD03126) 0.2 Normal Liver 0.0 Lung Cancer (OD04404) 0.0 Liver Cancer 0.1 Lung Margin (OD04404) 0.1 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 0.1 Liver Cancer 1026 0.0 Lung Margin (OD04565) 0.1 Liver Cancer 6004-T 0.0 Lung Cancer 0.0 Liver Tissue 6004-N 0.0 (OD04237-01) Lung Margin 0.0 Liver Cancer 6005-T 0.0 (OD04237-02) Ocular Mel Met to Liver 0.0 Liver Tissue 6005-N 0.0 (ODO4310) Liver Margin (ODO4310) 0.0 Normal Bladder 0.0 Melanoma Metastasis 0.0 Bladder Cancer 0.0 Lung Margin (OD04321) 0.0 Bladder Cancer 0.2 Normal Kidney 0.0 Bladder Cancer 0.0 (OD04718-01) Kidney Ca, Nuclear 0.0 Bladder Normal 0.0 grade 2 (OD04338) Adjacent (OD04718-03) Kidney Margin 0.0 Normal Ovary 0.0 (OD04338) Kidney Ca Nuclear grade 0.0 Ovarian Cancer 0.0 ½ (OD04339) Kidney Margin 0.0 Ovarian Cancer 0.0 (OD04339) (OD04768-07) Kidney Ca, Clear cell 0.1 Ovary Margin 0.0 type (OD04340) (OD04768-08) Kidney Margin 0.0 Normal Stomach 0.0 (OD04340) Kidney Ca, Nuclear grade 0.0 Gastric Cancer 0.0 3 (OD04348) 9060358 Kidney Margin 0.0 Stomach Margin 0.0 (OD04348) 9060359 Kidney Cancer 0.0 Gastric Cancer 0.0 (OD04622-01) 9060395 Kidney Margin 0.0 Stomach Margin 0.0 (OD04622-03) 9060394 Kidney Cancer 0.0 Gastric Cancer 0.0 (OD04450-01) 9060397 Kidney Margin 0.0 Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 8120607 0.0 Gastric Cancer 0.0 064005

[0759] TABLE 79 Panel 4D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag1478, Ag1478, Ag2501, Ag1478, Ag1478, Ag2501, Run Run Run Run Run Run Tissue Name 145909066 146946828 164318131 Tissue Name 145909066 146946828 164318131 Secondary Th1 act 0.0 0.0 0.0 HUVEC IL- 0.0 0.0 0.0 1beta Secondary Th2 act 0.0 0.0 0.0 HUVEC IFN 0.0 0.0 0.0 gamma Secondary Tr1 act 0.0 0.0 0.0 HUVEC TNF 0.0 0.0 0.0 alpha + IFN gamma Secondary Th1 0.0 0.0 0.0 HUVEC TNF 0.0 0.0 0.0 rest alpha + IL4 Secondary Th2 0.0 0.0 0.0 HUVEC IL-11 0.0 0.0 0.0 rest Secondary Tr1 0.0 0.0 0.0 Lung 0.0 0.0 0.0 rest Microvascular EC none Primary Th1 act 0.0 0.0 0.0 Lung 0.0 0.0 0.0 Microvascular EC TNFalpha + IL-1beta Primary Th2 act 0.0 0.0 0.0 Microvascular 0.0 0.0 0.0 Dermal EC none Primary Tr1 act 0.0 0.0 0.0 Microsvasular 0.0 0.0 0.0 Dermal EC TNFalpha + IL- 1beta Primary Th1 rest 0.0 0.0 0.0 Bronchial 0.0 0.0 0.0 epithelium TNFalpha + IL1beta Primary Th2 rest 0.0 0.0 0.0 Small airway 0.0 0.0 0.0 epithelium none Primary Tr1 rest 0.0 1.0 0.0 Small airway 0.0 0.0 0.0 epithelium TNFalpha + IL- 1beta CD45RA CD4 0.0 0.0 0.0 Coronery artery 0.0 0.0 0.0 lymphocyte act SMC rest CD45RO CD4 0.0 0.0 0.0 Coronery artery 0.0 0.0 0.0 lymphocyte act SMC TNFalpha + IL-1beta CD8 lymphocyte 0.0 0.0 0.0 Astrocytes rest 0.0 0.0 0.0 act Secondary CD8 0.0 0.0 0.0 Astrocytes 0.0 0.0 0.0 lymphocyte rest TNFalpha + IL- 1beta Secondary CD8 0.0 0.0 0.0 KU-812 10.0 15.1 13.4 lymphocyte act (Basophil) rest CD4 lymphocyte 0.9 0.0 0.0 KU-812 100.0 100.0 100.0 none (Basophil) PMA/ionomycin 2ry 0.0 0.0 0.0 CCD1106 0.0 0.0 0.0 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cells rest 0.0 1.0 1.3 CCD1106 0.0 0.0 0.0 (Keratinocytes) TNFalpha + IL- 1beta LAK cells IL-2 0.0 0.0 0.0 Liver cirrhosis 4.1 2.5 2.3 LAK cells IL- 0.0 0.0 0.0 Lupus kidney 0.0 0.0 0.0 2 + IL-12 LAK cells IL- 0.0 0.0 1.6 NCI-H292 none 0.0 0.0 0.0 2 + IFN gamma LAK cells IL-2 + 0.0 0.0 0.0 NCI-H292 IL-4 0.0 0.0 0.0 IL-18 LAK cells 1.4 0.0 1.3 NCI-H292 IL-9 0.0 0.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 0.9 NCI-H292 IL- 0.0 0.0 0.0 13 Two Way MLR 3 0.0 0.0 1.2 NCI-H292 IFN 0.0 0.0 0.0 day gamma Two Way MLR 5 0.0 0.0 0.0 HPAEC none 0.0 0.0 0.0 day Two Way MLR 7 0.0 0.0 0.0 HPAEC TNF 0.0 0.0 0.0 day alpha + IL-1 beta PBMC rest 0.0 1.9 0.0 Lung fibroblast 0.0 0.0 0.0 none PBMC PWM 7.4 0.0 2.0 Lung fibroblast 0.0 0.0 0.0 TNF alpha + IL- 1 beta PBMC PHA-L 0.0 0.0 2.6 Lung fibroblast 0.0 0.0 0.0 IL-4 Ramos (B cell) 0.0 0.0 0.0 Lung fibroblast 0.0 0.0 0.0 none IL-9 Ramos (B cell) 0.0 0.0 0.0 Lung fibroblast 0.0 0.0 0.0 ionomycin IL-13 B lymphocytes 0.0 0.0 0.0 Lung fibroblast 0.0 0.0 0.0 PWM IFN gamma B lymphocytes 0.0 0.0 0.0 Dermal 0.0 0.0 0.0 CD40L and IL-4 fibroblast CCD1070 rest EOL-1 dbcAMP 0.0 0.0 0.0 Dermal 0.0 0.0 0.0 fibroblast CCD1070 TNF alpha EOL-1 dbcAMP 0.0 0.0 0.0 Dermal 0.0 0.0 0.0 PMA/ionomycin fibroblast CCD1070 IL-1 beta Dendritic cells 0.0 0.0 0.0 Dermal 0.0 0.0 0.0 none fibroblast IFN gamma Dendritic cells 0.0 0.0 0.0 Dermal 0.0 0.0 0.0 LPS fibroblast IL-4 Dendritic cells 0.0 0.0 0.0 IBD Colitis 2 0.0 1.2 0.0 anti-CD40 Monocytes rest 0.0 0.0 0.0 IBD Crohn's 0.0 0.0 0.0 Monocytes LPS 0.0 0.0 0.0 Colon 0.0 1.3 0.0 Macrophages rest 0.0 0.0 0.0 Lung 0.0 0.0 0.0 Macrophages LPS 1.7 0.0 0.0 Thymus 1.1 0.0 0.0 HUVEC none 0.0 0.0 0.0 Kidney 0.6 0.0 1.6 HUVEC starved 0.0 0.0 0.0

[0760] CNS_neurodegeneration_v1.0 Summary Ag1478/Ag2501 Expression is low to undetectable (CT values>35) in all of the samples on this panel (data not shown).

[0761] Panel 1.3D Summary Ag1478/Ag2501 Expression is low to undetectable (CT values>35) in all of the examples on this panel (data not shown).

[0762] Panel 1.2 Summary: Ag1478 Highest expression is in a sample derive from a lung cancer cell line (CT=33.1). There is also significant expression in samples derived from an ovarian cancer cell line and a melanoma cell line. Thus, the GPCR13 gene may be involved in melanoma, or ovarianor lung cancer. Therefore, inhibition of the function of the protein encoded by this gene, through the use of antibodies or small molecule drugs, might be of use for the treatment of these diseases.

[0763] Panel 2D Summary: Ag1478 The expression of the GPCR13 gene is expressed highest and exclusively in normal prostate tissue. Thus, the expression of this gene could be used to distinguish normal prostate tissue from other tissues. A second run with the same probe and primer set showed low/undetectable levels of expression in all the samples in this panel.

[0764] Panel 4D Summary: Ag1478/Ag2501 Replicate experiments using different probe/primer sets all show that the GPCR13 transcript is induced in the PMA and ionomycin-treated basophil cell line KU-812. Basophils release histamines and other biological modifiers in repose to allergens and play an important role in the pathology of asthma and hypersensitivity reactions. Small molecule or antibody therapeutics designed against the putative GPCR encoded for by this gene could therefore reduce or inhibit inflammation by blocking basophil function in these diseases.

OTHER EMBODIMENTS

[0765] Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims.

1 205 1 953 DNA Homo sapiens 1 ctctgccatg atcattttca acctgagcag ttacaatcca ggacccttca ttctggtagg 60 gatcccaggc ctggagcaat tccatgtgtg gattggaatt cccttctgta tcatctacat 120 tgtagctgtt gtgggaaact gcatccttct ctacctcatt gtggtggagc atagtcttca 180 tgaacccatg ttcttctttc tctccatgct ggccatgact gacctcatct tgtccacagc 240 tggtgtgcct aaaacactca gtatcttttg gctaggggct cgcgaaatca cattcccagg 300 atgccttaca caaatgttct tccttcacta taactttgtc ctggattcag ccattctgat 360 ggccatggca tttgatcgct atgtagctat ctgttctccc ttgagatata ccaccatctt 420 gactcccaag accatcatca agagtgctat gggcatctcc tttcgaagct tctgcatcat 480 cctgccagat gtattcttgc tgacatgcct gcctttctgc aggacacgca tcatacccca 540 cacatactgt gagcatatag gtgttgccca gctcgcctgt gctgatatct ccatcaactt 600 ctggtatggc ttttgtgttc ccatcatgac agtcatctca gatgtgattc tcattgctgt 660 ttcctacgca cacatcctct gtgctgtctt ttgccttccc tcccaagatg cccgccagaa 720 agccctcggc acttgtggtt ctcatgtctg tgtcatcctc atgttttata cacctgcctt 780 tttctccatc ctcgcccatc gctttggaca caatgtctct cgcaccttcc acatcatgtt 840 tgccaatctc tacattgtta tcccacctgc actcaacccc atggtttacg gagtgaagac 900 caagcagatc agagataagg ttatactttt gttttctaag ggtacaggat gat 953 2 316 PRT Homo sapiens 2 Ser Ala Met Ile Ile Phe Asn Leu Ser Ser Tyr Asn Pro Gly Pro Phe 1 5 10 15 Ile Leu Val Gly Ile Pro Gly Leu Glu Gln Phe His Val Trp Ile Gly 20 25 30 Ile Pro Phe Cys Ile Ile Tyr Ile Val Ala Val Val Gly Asn Cys Ile 35 40 45 Leu Leu Tyr Leu Ile Val Val Glu His Ser Leu His Glu Pro Met Phe 50 55 60 Phe Phe Leu Ser Met Leu Ala Met Thr Asp Leu Ile Leu Ser Thr Ala 65 70 75 80 Gly Val Pro Lys Thr Leu Ser Ile Phe Trp Leu Gly Ala Arg Glu Ile 85 90 95 Thr Phe Pro Gly Cys Leu Thr Gln Met Phe Phe Leu His Tyr Asn Phe 100 105 110 Val Leu Asp Ser Ala Ile Leu Met Ala Met Ala Phe Asp Arg Tyr Val 115 120 125 Ala Ile Cys Ser Pro Leu Arg Tyr Thr Thr Ile Leu Thr Pro Lys Thr 130 135 140 Ile Ile Lys Ser Ala Met Gly Ile Ser Phe Arg Ser Phe Cys Ile Ile 145 150 155 160 Leu Pro Asp Val Phe Leu Leu Thr Cys Leu Pro Phe Cys Arg Thr Arg 165 170 175 Ile Ile Pro His Thr Tyr Cys Glu His Ile Gly Val Ala Gln Leu Ala 180 185 190 Cys Ala Asp Ile Ser Ile Asn Phe Trp Tyr Gly Phe Cys Val Pro Ile 195 200 205 Met Thr Val Ile Ser Asp Val Ile Leu Ile Ala Val Ser Tyr Ala His 210 215 220 Ile Leu Cys Ala Val Phe Cys Leu Pro Ser Gln Asp Ala Arg Gln Lys 225 230 235 240 Ala Leu Gly Thr Cys Gly Ser His Val Cys Val Ile Leu Met Phe Tyr 245 250 255 Thr Pro Ala Phe Phe Ser Ile Leu Ala His Arg Phe Gly His Asn Val 260 265 270 Ser Arg Thr Phe His Ile Met Phe Ala Asn Leu Tyr Ile Val Ile Pro 275 280 285 Pro Ala Leu Asn Pro Met Val Tyr Gly Val Lys Thr Lys Gln Ile Arg 290 295 300 Asp Lys Val Ile Leu Leu Phe Ser Lys Gly Thr Gly 305 310 315 3 953 DNA Homo sapiens 3 ctctgccatg atcattttca acctgagcag ttacaatcca ggacccttca ttctggtagg 60 gatcccaggc ctggagcaat tccatgtgtg gattggaatt cccttctgta tcatctacat 120 tgtagctgtt gtgggaaact gcatccttct ctacctcatt gtggtggagc atagtcttca 180 tgaacccatg ttcttctttc tctccatgct ggccatgact gacctcatct tgtccacagc 240 tggtgtgcct aaaacactca gtatcttttg gctaggggct cgcgaaatca cattcccagg 300 atgccttaca caaatgttct tccttcacta taactttgtc ctggattcag ccattctgat 360 ggccatggca tttgatcgct atgtagctat ctgttctccc ttgagatata ccaccatctt 420 gactcccaag accatcatca agagtgctat gggcatctcc tttcgaagct tctgcatcat 480 cctgccagat gtattcttgc tgacatgcct gcctttctgc aggacacgca tcatacccca 540 cacatactgt gagcatatag gtgttgcccg gctcgcctgt gctgatatct ccatcaactt 600 ctggtatggc ttttgtgttc ccatcatgac agtcatctca gatgtgattc tcattgctgt 660 ttcctacgca cacatcctct gtgctgtctt ttgccttccc tcccaagatg cccgccagaa 720 agccctcggc acttgtggtt ctcatgtctg tgtcatcctc atgttttata cacctgcctt 780 tttctccatc ctcgcccatc gctttggaca caatgtctct cgcaccttcc acatcatgtt 840 tgccaatctc tacattgtta tcccacctgc actcaacccc atggtttacg gagtgaagac 900 caagcagatc agagataagg ttatactttt gttttctaag ggtacaggat gat 953 4 314 PRT Homo sapiens 4 Met Ile Ile Phe Asn Leu Ser Ser Tyr Asn Pro Gly Pro Phe Ile Leu 1 5 10 15 Val Gly Ile Pro Gly Leu Glu Gln Phe His Val Trp Ile Gly Ile Pro 20 25 30 Phe Cys Ile Ile Tyr Ile Val Ala Val Val Gly Asn Cys Ile Leu Leu 35 40 45 Tyr Leu Ile Val Val Glu His Ser Leu His Glu Pro Met Phe Phe Phe 50 55 60 Leu Ser Met Leu Ala Met Thr Asp Leu Ile Leu Ser Thr Ala Gly Val 65 70 75 80 Pro Lys Thr Leu Ser Ile Phe Trp Leu Gly Ala Arg Glu Ile Thr Phe 85 90 95 Pro Gly Cys Leu Thr Gln Met Phe Phe Leu His Tyr Asn Phe Val Leu 100 105 110 Asp Ser Ala Ile Leu Met Ala Met Ala Phe Asp Arg Tyr Val Ala Ile 115 120 125 Cys Ser Pro Leu Arg Tyr Thr Thr Ile Leu Thr Pro Lys Thr Ile Ile 130 135 140 Lys Ser Ala Met Gly Ile Ser Phe Arg Ser Phe Cys Ile Ile Leu Pro 145 150 155 160 Asp Val Phe Leu Leu Thr Cys Leu Pro Phe Cys Arg Thr Arg Ile Ile 165 170 175 Pro His Thr Tyr Cys Glu His Ile Gly Val Ala Arg Leu Ala Cys Ala 180 185 190 Asp Ile Ser Ile Asn Phe Trp Tyr Gly Phe Cys Val Pro Ile Met Thr 195 200 205 Val Ile Ser Asp Val Ile Leu Ile Ala Val Ser Tyr Ala His Ile Leu 210 215 220 Cys Ala Val Phe Cys Leu Pro Ser Gln Asp Ala Arg Gln Lys Ala Leu 225 230 235 240 Gly Thr Cys Gly Ser His Val Cys Val Ile Leu Met Phe Tyr Thr Pro 245 250 255 Ala Phe Phe Ser Ile Leu Ala His Arg Phe Gly His Asn Val Ser Arg 260 265 270 Thr Phe His Ile Met Phe Ala Asn Leu Tyr Ile Val Ile Pro Pro Ala 275 280 285 Leu Asn Pro Met Val Tyr Gly Val Lys Thr Lys Gln Ile Arg Asp Lys 290 295 300 Val Ile Leu Leu Phe Ser Lys Gly Thr Gly 305 310 5 953 DNA Homo sapiens 5 ctctgccatg atcattttca acctgagcag ttacaatcca ggacccttca ttctggtagg 60 gatcccaggc ctggagcaat tccatgtgtg gattggaatt cccttctgta tcatctacat 120 tgtagctgtt gtgggaaact gcatccttct ctacctcatt gtggtggagc atagtcttca 180 tgaacccatg ttcttctttc tctccatgct ggccatgact gacctcatct tgtccacagc 240 tggtgtgcct aaaacactca gtatcttttg gctaggggct cgcgaaatca cattcccagg 300 atgccttaca caaatgttct tccttcacta taactttgtc ctggattcag ccattctgat 360 ggccatggca tttgatcact atgtagctat ctgttctccc ttgagatata ccaccatctt 420 gactcccaag accatcatca agagtgctat gggcatctcc tttcgaagct tctgcatcat 480 cctgccagat gtattcttgc tgacatgcct gcctttctgc aggacacgca tcatacccca 540 cacatactgt gagcatatgg gtgttgccca gctcgcctgt gctgatatct ccatcaactt 600 ctggtatggc ttttgtgttc ccatcatgac agtcatctca gatgtgattc tcattgctgt 660 ttcctacgca cacatcctct gtgctgtctt ttgccttccc tcccaagatg cccgccagaa 720 ggccctcggc acttgtggtt ctcatgtctg tgtcatcctc atgttttata cacctgcctt 780 tttctccatc ctcgcccatc gctttggaca caatgtctct cgcaccttcc acatcatgtt 840 tgccaatctc tacattgtta tcccacctgc actcaacccc atggtttacg gagtgaagac 900 caagcagatc agagataagg ttatactttt gttttctaag ggtacaggat gat 953 6 314 PRT Homo sapiens 6 Met Ile Ile Phe Asn Leu Ser Ser Tyr Asn Pro Gly Pro Phe Ile Leu 1 5 10 15 Val Gly Ile Pro Gly Leu Glu Gln Phe His Val Trp Ile Gly Ile Pro 20 25 30 Phe Cys Ile Ile Tyr Ile Val Ala Val Val Gly Asn Cys Ile Leu Leu 35 40 45 Tyr Leu Ile Val Val Glu His Ser Leu His Glu Pro Met Phe Phe Phe 50 55 60 Leu Ser Met Leu Ala Met Thr Asp Leu Ile Leu Ser Thr Ala Gly Val 65 70 75 80 Pro Lys Thr Leu Ser Ile Phe Trp Leu Gly Ala Arg Glu Ile Thr Phe 85 90 95 Pro Gly Cys Leu Thr Gln Met Phe Phe Leu His Tyr Asn Phe Val Leu 100 105 110 Asp Ser Ala Ile Leu Met Ala Met Ala Phe Asp His Tyr Val Ala Ile 115 120 125 Cys Ser Pro Leu Arg Tyr Thr Thr Ile Leu Thr Pro Lys Thr Ile Ile 130 135 140 Lys Ser Ala Met Gly Ile Ser Phe Arg Ser Phe Cys Ile Ile Leu Pro 145 150 155 160 Asp Val Phe Leu Leu Thr Cys Leu Pro Phe Cys Arg Thr Arg Ile Ile 165 170 175 Pro His Thr Tyr Cys Glu His Met Gly Val Ala Gln Leu Ala Cys Ala 180 185 190 Asp Ile Ser Ile Asn Phe Trp Tyr Gly Phe Cys Val Pro Ile Met Thr 195 200 205 Val Ile Ser Asp Val Ile Leu Ile Ala Val Ser Tyr Ala His Ile Leu 210 215 220 Cys Ala Val Phe Cys Leu Pro Ser Gln Asp Ala Arg Gln Lys Ala Leu 225 230 235 240 Gly Thr Cys Gly Ser His Val Cys Val Ile Leu Met Phe Tyr Thr Pro 245 250 255 Ala Phe Phe Ser Ile Leu Ala His Arg Phe Gly His Asn Val Ser Arg 260 265 270 Thr Phe His Ile Met Phe Ala Asn Leu Tyr Ile Val Ile Pro Pro Ala 275 280 285 Leu Asn Pro Met Val Tyr Gly Val Lys Thr Lys Gln Ile Arg Asp Lys 290 295 300 Val Ile Leu Leu Phe Ser Lys Gly Thr Gly 305 310 7 965 DNA Homo sapiens 7 ccccttgtct cctcacacaa tgaccctggg atccctggga aacagcagca gcagcgtttc 60 tgctaccttc ctgctgaggg catccctggg ctggagcgca tgcacatctg gatctccatc 120 ccactgtgct tcatgtatct ggtttccatc ccgggcaact gcacaattct ttttatcatt 180 aaaacagagc gctcacttca tgaacctatg tatctcttcc tgtccatgct ggctctgatt 240 gacctgggtc tctccctttg cactctccct acagtcctgg gcatcttttg ggttggagca 300 cgagaaatta gccatgatgc ctgctttgct cagctctttt tcattcactg cttctccttc 360 ctcgagtcct ctgtgctact gtctatggcc tttgaccgct ttgtggctat ctgccacccc 420 ttgcactatg tttccattct caccaacaca gtcattggca ggattggcct ggtctctctg 480 ggtcgtagtg tagcactcat ttttccatta ccttttatgc tcaaaagatt cccctattgt 540 ggctccccag ttctctcaca ttcttattgt ctccaccaag aagtgatgaa attggcctgt 600 gccgacatga aggccaacag catctacggc atgtttgtca tcgtctctac agtgggtata 660 gactcactgc tcatcctctt ctcttatgct ctgatcctgc gcaccgtgct gtccatcgcc 720 tccagggctg agagattcaa ggcccttaac acctgtgttt cccacatctg tgctgtgctg 780 ctcttctaca ctcccatgat tggcctctct gtcatccatc gctttggaaa gcaggcaccc 840 cacctggtcc aggtggtcat gggtttcatg tatcttctct ttcctcctgt gatgaatccc 900 attgtctaca gtgtgaagac caaacagatc cgggatcgag tgacgcatgc cttttgttac 960 taact 965 8 314 PRT Homo sapiens 8 Met Thr Leu Gly Ser Leu Gly Asn Ser Ser Ser Ser Val Ser Ala Thr 1 5 10 15 Phe Leu Leu Ser Gly Ile Pro Gly Leu Glu Arg Met His Ile Trp Ile 20 25 30 Ser Ile Pro Leu Cys Phe Met Tyr Leu Val Ser Ile Pro Gly Asn Cys 35 40 45 Thr Ile Leu Phe Ile Ile Lys Thr Glu Arg Ser Leu His Glu Pro Met 50 55 60 Tyr Leu Phe Leu Ser Met Leu Ala Leu Ile Asp Leu Gly Leu Ser Leu 65 70 75 80 Cys Thr Leu Pro Thr Val Leu Gly Ile Phe Trp Val Gly Ala Arg Glu 85 90 95 Ile Ser His Asp Ala Cys Phe Ala Gln Leu Phe Phe Ile His Cys Phe 100 105 110 Ser Phe Leu Glu Ser Ser Val Leu Leu Ser Met Ala Phe Asp Arg Phe 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Val Ser Ile Leu Thr Asn Thr 130 135 140 Val Ile Gly Arg Ile Gly Leu Val Ser Leu Gly Arg Ser Val Ala Leu 145 150 155 160 Ile Phe Pro Leu Pro Phe Met Leu Lys Arg Phe Pro Tyr Cys Gly Ser 165 170 175 Pro Val Leu Ser His Ser Tyr Cys Leu His Gln Glu Val Met Lys Leu 180 185 190 Ala Cys Ala Asp Met Lys Ala Asn Ser Ile Tyr Gly Met Phe Val Ile 195 200 205 Val Ser Thr Val Gly Ile Asp Ser Leu Leu Ile Leu Phe Ser Tyr Ala 210 215 220 Leu Ile Leu Arg Thr Val Leu Ser Ile Ala Ser Arg Ala Glu Arg Phe 225 230 235 240 Lys Ala Leu Asn Thr Cys Val Ser His Ile Cys Ala Val Leu Leu Phe 245 250 255 Tyr Thr Pro Met Ile Gly Leu Ser Val Ile His Arg Phe Gly Lys Gln 260 265 270 Ala Pro His Leu Val Gln Val Val Met Gly Phe Met Tyr Leu Leu Phe 275 280 285 Pro Pro Val Met Asn Pro Ile Val Tyr Ser Val Lys Thr Lys Gln Ile 290 295 300 Arg Asp Arg Val Thr His Ala Phe Cys Tyr 305 310 9 966 DNA Homo sapiens 9 ccccttgtct cctcacacaa tgaccctggg atccctggga aacagcagca gcagcgtttc 60 tgctaccttc ctgctgagtg gcatccctgg gctggagcgc atgcacatct ggatctccat 120 cccactgtgc ttcatgtatc tggtttccat cccgggcaac tgcacaattc tttttatcat 180 taaaacagag cgctcacttc atgaacctat gtatctcttc ctgtccatgc tggctctgat 240 tgacctgggt ctctcccttt gcactctccc tacagtcctg ggcatctttt gggttggagc 300 acgacaaatt agccatgatg cctgctttgc tcagctcttt ttcattcact gcttctcctt 360 cctcgagtcc tctgtgctac tgtctatggc ctttgaccgc tttgtggcta tctgccaccc 420 cttgcactat gtttccattc tcaccaacac agtcattggc aggattggcc tggtctctct 480 gggtcgtagt gtagcactca tttttccatt accttttatg ctcaaaagat tcccctattg 540 tggctcccca gttctctcac attcttattg tctccaccaa gaagtgatga aattggcctg 600 tgccgacatg aaggccaaca gcatctacgg catgtttgtc atcgtctcta cagtgggtat 660 agactcactg ctcatcctct tctcttatgc tctgatcctg cgcaccgtgc tgtccatcgc 720 ctccagggct gagagattca aggcccttaa cacctgtgtt tcccacatct gtgctgtgct 780 gctcttctac actcccatga ttggcctctc tgtcatccat cgctttggaa agcaggcacc 840 ccacctggtc caggtggtca tgggtttcat gtatcttctc tttcctcctg tgatgaatcc 900 cattgtctac agtgtgaaga ccaaacagat ccgggatcga gtgacgcatg ccttttgtta 960 ctaact 966 10 314 PRT Homo sapiens 10 Met Thr Leu Gly Ser Leu Gly Asn Ser Ser Ser Ser Val Ser Ala Thr 1 5 10 15 Phe Leu Leu Ser Gly Ile Pro Gly Leu Glu Arg Met His Ile Trp Ile 20 25 30 Ser Ile Pro Leu Cys Phe Met Tyr Leu Val Ser Ile Pro Gly Asn Cys 35 40 45 Thr Ile Leu Phe Ile Ile Lys Thr Glu Arg Ser Leu His Glu Pro Met 50 55 60 Tyr Leu Phe Leu Ser Met Leu Ala Leu Ile Asp Leu Gly Leu Ser Leu 65 70 75 80 Cys Thr Leu Pro Thr Val Leu Gly Ile Phe Trp Val Gly Ala Arg Gln 85 90 95 Ile Ser His Asp Ala Cys Phe Ala Gln Leu Phe Phe Ile His Cys Phe 100 105 110 Ser Phe Leu Glu Ser Ser Val Leu Leu Ser Met Ala Phe Asp Arg Phe 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Val Ser Ile Leu Thr Asn Thr 130 135 140 Val Ile Gly Arg Ile Gly Leu Val Ser Leu Gly Arg Ser Val Ala Leu 145 150 155 160 Ile Phe Pro Leu Pro Phe Met Leu Lys Arg Phe Pro Tyr Cys Gly Ser 165 170 175 Pro Val Leu Ser His Ser Tyr Cys Leu His Gln Glu Val Met Lys Leu 180 185 190 Ala Cys Ala Asp Met Lys Ala Asn Ser Ile Tyr Gly Met Phe Val Ile 195 200 205 Val Ser Thr Val Gly Ile Asp Ser Leu Leu Ile Leu Phe Ser Tyr Ala 210 215 220 Leu Ile Leu Arg Thr Val Leu Ser Ile Ala Ser Arg Ala Glu Arg Phe 225 230 235 240 Lys Ala Leu Asn Thr Cys Val Ser His Ile Cys Ala Val Leu Leu Phe 245 250 255 Tyr Thr Pro Met Ile Gly Leu Ser Val Ile His Arg Phe Gly Lys Gln 260 265 270 Ala Pro His Leu Val Gln Val Val Met Gly Phe Met Tyr Leu Leu Phe 275 280 285 Pro Pro Val Met Asn Pro Ile Val Tyr Ser Val Lys Thr Lys Gln Ile 290 295 300 Arg Asp Arg Val Thr His Ala Phe Cys Tyr 305 310 11 1251 DNA Homo sapiens 11 caaaatgatt atagctgaca aaatcaggaa gtgtgttgtt aacttcctga cttcttatat 60 ttcagagaac gaagagttga accatttaac atgaattggg taaataagag tgtcccacag 120 gagttcattc tgttagtttt ctcagatcaa ccatggctag agattccacc ctttgtgatg 180 tttctgtttt cctatatctt gacaatcttt ggcaatctga caataattct tgtgtcacat 240 gtggatttca aactccacac ccctatgtac ttttttctta gcaatctctc actcctggac 300 ctttgctata ccacaagtac agttccacaa atgctggtaa acatatgcaa caccaggaaa 360 gtaatcagtt atggtggctg tgtggcccag cttttcattt tcctggcctt gggttccaca 420 gaatgtcttc tcctggccgt catgtgcttt gataggtttg tagctatttg tcggcctctc 480 cattactcaa ttatcatgca ccagaggctc tgcttccagt tggcagctgc atcctggatt 540 agtggcttta gcaattcagt attacagtcc acctggacac ttaagatgcc actgtgtggt 600 cacaaagaag tggatcactt cttctgtgaa gtccctgctc tgctcaagtt gtcctgtgtt 660 gacacaacag caaatgaggc tgaactattc ttcatcagtg tgctattcct tctaataccc 720 gtgacactca tccttatatc gtatgctttt attgtccaag cagtgttgag aatccagtct 780 gctgaaggtc aacgaaaggc atttgggaca tgtggctccc atctaattgt ggtgtcactt 840 ttttatggta cagctatctc catgtacctg caaccacctt cacccagctc caaagaccgg 900 ggaaagatgg tttctctctt ctgtggaatc attgcaccca tgctgaatcc ccttatatat 960 acacttagga acaaagaggt aaaggaagcc tttaaaaggt tggttgcaaa gagtcttctt 1020 aatcaagaaa taagaaatat gcaaatgata agctttgcta aagacacagt gcttacttac 1080 cttactaact tctccgcaag ttgtcctatt tttgtcatta ctatagaaaa ctattgtaat 1140 ctccctcaaa gaaaatttcc ttgacaaaaa gctatatttg tttctgttgc ctaaacattt 1200 tcattgaaca agcccccaga attggccttc caatgcacca aaaactgtaa t 1251 12 357 PRT Homo sapiens 12 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Gln Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu Asn Gln Glu Ile Arg Asn Met Gln Met Ile 305 310 315 320 Ser Phe Ala Lys Asp Thr Val Leu Thr Tyr Leu Thr Asn Phe Ser Ala 325 330 335 Ser Cys Pro Ile Phe Val Ile Thr Ile Glu Asn Tyr Cys Asn Leu Pro 340 345 350 Gln Arg Lys Phe Pro 355 13 953 DNA Homo sapiens 13 gcctgaccaa aaagaatggc agccaaaaac tcttctgtga cagagtttat cctcgaaggc 60 ttaacccacc agccgggact gcggatcccc ctcttcttcc tgtttctggg tttctacacg 120 gtcaccgtgg tggggaacct gggcttgata accctgattg ggctgaactc tcacctgcac 180 actcccatgt acttcttcct ttttaacctc tctttaatag atttctgttt ctccactacc 240 atcactccca aaatgctgat gagttttgtc tcaaggaaga acatcatttc cttcacaggg 300 tgtatgactc agctcttctt cttctgcttc tttgtcgtct ctgagtcctt catcctgtca 360 gcgatggcgt atgaccgcta cgtggccatc tgtaacccac tgttgtacac agtcaccatg 420 tcttgccagg tgtgtttgct ccttttgttg ggtgcctatg ggatggggtt tgctggggcc 480 atggcccaca caggaagcat aatgaacctg accttctgtg ctgacaacct tgtcaatcat 540 ttcatgtgtg acatccttcc tctccttgag ctctcctgca acagctctta catgaatgag 600 ccggtggtct ttattgtggt ggctgttgac gttggaatgc ccattgtcac tgtctttatt 660 tcttatgccc tcatcctctc cagcattcta cacaacagtt ctacagaagg caggtccaaa 720 gcctttagta cttgcagttc ccacataatt gtagtttctc ttttctttgg ttctggtgct 780 ttcatgtatc tcaaacccct ttccatcctg cccctcgagc aagggaaagt gtcctccctg 840 ttctatacca taatagtccc cgtgttaaac ccattaatct atagcttgag gaacaaggat 900 gtcaaagttg ccctgaggag aactttgggc agaaaaatct tttcttaaga aag 953 14 310 PRT Homo sapiens 14 Met Ala Ala Lys Asn Ser Ser Val Thr Glu Phe Ile Leu Glu Gly Leu 1 5 10 15 Thr His Gln Pro Gly Leu Arg Ile Pro Leu Phe Phe Leu Phe Leu Gly 20 25 30 Phe Tyr Thr Val Thr Val Val Gly Asn Leu Gly Leu Ile Thr Leu Ile 35 40 45 Gly Leu Asn Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Phe Asn 50 55 60 Leu Ser Leu Ile Asp Phe Cys Phe Ser Thr Thr Ile Thr Pro Lys Met 65 70 75 80 Leu Met Ser Phe Val Ser Arg Lys Asn Ile Ile Ser Phe Thr Gly Cys 85 90 95 Met Thr Gln Leu Phe Phe Phe Cys Phe Phe Val Val Ser Glu Ser Phe 100 105 110 Ile Leu Ser Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro 115 120 125 Leu Leu Tyr Thr Val Thr Met Ser Cys Gln Val Cys Leu Leu Leu Leu 130 135 140 Leu Gly Ala Tyr Gly Met Gly Phe Ala Gly Ala Met Ala His Thr Gly 145 150 155 160 Ser Ile Met Asn Leu Thr Phe Cys Ala Asp Asn Leu Val Asn His Phe 165 170 175 Met Cys Asp Ile Leu Pro Leu Leu Glu Leu Ser Cys Asn Ser Ser Tyr 180 185 190 Met Asn Glu Pro Val Val Phe Ile Val Val Ala Val Asp Val Gly Met 195 200 205 Pro Ile Val Thr Val Phe Ile Ser Tyr Ala Leu Ile Leu Ser Ser Ile 210 215 220 Leu His Asn Ser Ser Thr Glu Gly Arg Ser Lys Ala Phe Ser Thr Cys 225 230 235 240 Ser Ser His Ile Ile Val Val Ser Leu Phe Phe Gly Ser Gly Ala Phe 245 250 255 Met Tyr Leu Lys Pro Leu Ser Ile Leu Pro Leu Glu Gln Gly Lys Val 260 265 270 Ser Ser Leu Phe Tyr Thr Ile Ile Val Pro Val Leu Asn Pro Leu Ile 275 280 285 Tyr Ser Leu Arg Asn Lys Asp Val Lys Val Ala Leu Arg Arg Thr Leu 290 295 300 Gly Arg Lys Ile Phe Ser 305 310 15 1103 DNA Homo sapiens misc_feature (51) where n is A, G, C or T 15 tgcagatttt atcttctttc tacctctgtg agtagaaggt gaggttctga nagttctccc 60 cagctatgcc tactgtaaac cacagtggca ctagccacac agtcttccac ttgctgggca 120 tccctggcct acaggaccag cacatgtgga tttctatccc attcttcatt tcctatgtca 180 ccgcccttct tgggaacagc ctgctcatct tcattatcct cacaaagcgc agcctccatg 240 aacccatgta cctcttcctc tgcatgctgg ctggagcaga cattgtcctc tccacgtgca 300 ccattcctca ggccttagct atcttctggt tccgtgctgg ggacatctcc ctggatcgtt 360 gcatcactca gctcttcttc atccattcca ccttcatctc tgagtcaggg atcttgctgg 420 tgatggcctt tgaccactat attgccatat gctacccact gaggtacacc accattctta 480 caaatgctct gatcaagaaa atttgtgtga ctgtctctct gagaagttat ggtacaattt 540 tccctatcat atttctttta aaaagattga ctttctgcca gaataatatt attccacaca 600 ccttttgtga acacattggc ctagccaaat atgcatgtaa tgacattcga ataaacattt 660 ggtatgggtt ttccattcta atgtcgacgg tggtcttaga tgttgtacta atttttattt 720 cctatatgct gattctccat gctgtcttcc acatgccttc tccagatgct tgccacaaag 780 ctctcaacac atttggctcc catgtctgca tcatcatcct cttttatggg tctggcatct 840 tcacaatcct tacccagagg tttggacgcc acattccacc ttgtatccac atcccgttgg 900 ctaatgtctg cattctggct ccacctatgc tgaatcccat tatttatggg atcaaaacca 960 agcaaatcca ggaacaggtg gttcagtttt tgtttataaa acagaaaata actttggttt 1020 aagaactgag ttttcagaat ctctagctat ctggtaagtg ggtatgaaag tggtagatgg 1080 gagaggtcag ctgataccgt aga 1103 16 318 PRT Homo sapiens 16 Met Pro Thr Val Asn His Ser Gly Thr Ser His Thr Val Phe His Leu 1 5 10 15 Leu Gly Ile Pro Gly Leu Gln Asp Gln His Met Trp Ile Ser Ile Pro 20 25 30 Phe Phe Ile Ser Tyr Val Thr Ala Leu Leu Gly Asn Ser Leu Leu Ile 35 40 45 Phe Ile Ile Leu Thr Lys Arg Ser Leu His Glu Pro Met Tyr Leu Phe 50 55 60 Leu Cys Met Leu Ala Gly Ala Asp Ile Val Leu Ser Thr Cys Thr Ile 65 70 75 80 Pro Gln Ala Leu Ala Ile Phe Trp Phe Arg Ala Gly Asp Ile Ser Leu 85 90 95 Asp Arg Cys Ile Thr Gln Leu Phe Phe Ile His Ser Thr Phe Ile Ser 100 105 110 Glu Ser Gly Ile Leu Leu Val Met Ala Phe Asp His Tyr Ile Ala Ile 115 120 125 Cys Tyr Pro Leu Arg Tyr Thr Thr Ile Leu Thr Asn Ala Leu Ile Lys 130 135 140 Lys Ile Cys Val Thr Val Ser Leu Arg Ser Tyr Gly Thr Ile Phe Pro 145 150 155 160 Ile Ile Phe Leu Leu Lys Arg Leu Thr Phe Cys Gln Asn Asn Ile Ile 165 170 175 Pro His Thr Phe Cys Glu His Ile Gly Leu Ala Lys Tyr Ala Cys Asn 180 185 190 Asp Ile Arg Ile Asn Ile Trp Tyr Gly Phe Ser Ile Leu Met Ser Thr 195 200 205 Val Val Leu Asp Val Val Leu Ile Phe Ile Ser Tyr Met Leu Ile Leu 210 215 220 His Ala Val Phe His Met Pro Ser Pro Asp Ala Cys His Lys Ala Leu 225 230 235 240 Asn Thr Phe Gly Ser His Val Cys Ile Ile Ile Leu Phe Tyr Gly Ser 245 250 255 Gly Ile Phe Thr Ile Leu Thr Gln Arg Phe Gly Arg His Ile Pro Pro 260 265 270 Cys Ile His Ile Pro Leu Ala Asn Val Cys Ile Leu Ala Pro Pro Met 275 280 285 Leu Asn Pro Ile Ile Tyr Gly Ile Lys Thr Lys Gln Ile Gln Glu Gln 290 295 300 Val Val Gln Phe Leu Phe Ile Lys Gln Lys Ile Thr Leu Val 305 310 315 17 972 DNA Homo sapiens 17 aaacttggac gatcgacatg gaaattgtct ccacaggaaa cgaaactatt actgaatttg 60 tcctccttgg cttctatgac atccctgaac tgcatttctt gttttttatt gtattcactg 120 ctgtctatgt cttcatcatc atagggaata tgctgattat tgtagcagtg gttagctccc 180 agaggctcca caaacccatg tatattttct tggcgaatct gtccttcctg gatattctct 240 acacctccgc agtgatgcca aaaatgctgg agggcttcct gcaagaagca actatctctg 300 tggctggttg cttgctccag ttctttatct tcggctctct agccacagct gaatgcttac 360 tgctggctgt catggcatat gaccgctacc tggcaatttg ctacccactc cactacccac 420 tcctgatggg gcccagacgg tacatggggc tggtggtcac aacctggctc tctggatttg 480 tggtagatgg actggttgtg gccctggtgg cccagctgag gttctgtggc cccaaccaca 540 ttgaccagtt ttactgtgac tttatgcttt tcgtgggcct ggcttgctcg gatcccagag 600 tggctcaggt gacaactctc attctgtctg tgttctgcct cactattcct tttggactga 660 ttctgacatc ttatgccaga attgtggtgg cagtgctgag agttcctgct ggggcaagca 720 ggagaagggc tttctccaca tgctcctccc acctagctgt agtgaccaca ttctatggaa 780 cgctcatgat cttttatgtt gcaccctctg ctgtccattc ccagctcctc tccaaggtct 840 tctccctgct ctacactgtg gtcacccctc tcttcaatcc tgtgatctat accatgagga 900 acaaggaggt gcatcaggca cttcggaaga ttctctgtat caaacaaact gaaacacttg 960 attgaaggag ag 972 18 315 PRT Homo sapiens 18 Met Glu Ile Val Ser Thr Gly Asn Glu Thr Ile Thr Glu Phe Val Leu 1 5 10 15 Leu Gly Phe Tyr Asp Ile Pro Glu Leu His Phe Leu Phe Phe Ile Val 20 25 30 Phe Thr Ala Val Tyr Val Phe Ile Ile Ile Gly Asn Met Leu Ile Ile 35 40 45 Val Ala Val Val Ser Ser Gln Arg Leu His Lys Pro Met Tyr Ile Phe 50 55 60 Leu Ala Asn Leu Ser Phe Leu Asp Ile Leu Tyr Thr Ser Ala Val Met 65 70 75 80 Pro Lys Met Leu Glu Gly Phe Leu Gln Glu Ala Thr Ile Ser Val Ala 85 90 95 Gly Cys Leu Leu Gln Phe Phe Ile Phe Gly Ser Leu Ala Thr Ala Glu 100 105 110 Cys Leu Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr Leu Ala Ile Cys 115 120 125 Tyr Pro Leu His Tyr Pro Leu Leu Met Gly Pro Arg Arg Tyr Met Gly 130 135 140 Leu Val Val Thr Thr Trp Leu Ser Gly Phe Val Val Asp Gly Leu Val 145 150 155 160 Val Ala Leu Val Ala Gln Leu Arg Phe Cys Gly Pro Asn His Ile Asp 165 170 175 Gln Phe Tyr Cys Asp Phe Met Leu Phe Val Gly Leu Ala Cys Ser Asp 180 185 190 Pro Arg Val Ala Gln Val Thr Thr Leu Ile Leu Ser Val Phe Cys Leu 195 200 205 Thr Ile Pro Phe Gly Leu Ile Leu Thr Ser Tyr Ala Arg Ile Val Val 210 215 220 Ala Val Leu Arg Val Pro Ala Gly Ala Ser Arg Arg Arg Ala Phe Ser 225 230 235 240 Thr Cys Ser Ser His Leu Ala Val Val Thr Thr Phe Tyr Gly Thr Leu 245 250 255 Met Ile Phe Tyr Val Ala Pro Ser Ala Val His Ser Gln Leu Leu Ser 260 265 270 Lys Val Phe Ser Leu Leu Tyr Thr Val Val Thr Pro Leu Phe Asn Pro 275 280 285 Val Ile Tyr Thr Met Arg Asn Lys Glu Val His Gln Ala Leu Arg Lys 290 295 300 Ile Leu Cys Ile Lys Gln Thr Glu Thr Leu Asp 305 310 315 19 1383 DNA Homo sapiens 19 tagaaatgga acgaccacaa agtgatttta accaaactga agttgctgaa tttttcctca 60 tgggattttc gaattcctgg gatattcaga ttgtacatgc tgctctattc ttcctagttt 120 acctggcagc tgtcatagga aatctcctaa tcatcatact taccactctg gatgttcacc 180 tccaaacccc aatgtatttc tttttgagaa acttgtcttt cttagatttt tgttacatct 240 ctgtcacaat tccaaaatct attgttagtt ccttgactca tgatacttcc atttctttct 300 ttgggtgtgc tctgcaagcc ttctttttca tggacttggc aactacggag gtagccatcc 360 ttacagtgat gtcctatgac cgctatatgg ccatctgccg gcctttacat tatgaggtca 420 tcataaacca aggtgtctgt ctgaggatga tggccatgtc gtggctcagt ggggtgatct 480 gtggattcat gcatgtgata gcaacattct cattaccatt ctgtgggcgc aatagaatac 540 gtcaattttt ctgtaatatt ccacagctcc taagcctctt agaccccaaa gtaattacca 600 ttgagattgg agtcatggtt tttggtacaa gtcttgtgat aatctccttt gttgtaatta 660 ctctctccta catgtacatt ttttctgtca tcatgaggat tccttctaag gagggtagat 720 caaaaacatt ttctacctgc attccacatc ttgtggttgt aacactcttt atgatatctg 780 gcagcattgc ctatgtgaag ccaatttcaa attctccccc cgttctggat gttttcctgt 840 ctgcgttcta cacagtcgtg cccccgaccc tgaaccccgt catctatagt ctgaggaata 900 gggacatgaa ggcagccctg agaaggcagt gtggtccctg agaaggcagt gtggtatgct 960 agatgaagaa tttgattacg gaccagactc ttgaactctt gctctaatca ggcaatttgt 1020 aaactctctg ggcttatatt ttcaattgat tgctgagctc tttcttgatt tttaaattaa 1080 attcagctat agtttaccat actaaccata tttgggtgaa ttcaacctta gaatgcacta 1140 aaaggtactt cggggtgttc aaaacattag aacttgtgct tttattcatt tttatgagtt 1200 gtagatctca aaattttata aattatattg tactcagtaa tacaacatat taattaatat 1260 aaaagtgaat tactaatata aatgaattac taccgtatgt gtatattaat tacagcagaa 1320 caagatcata tggattaaaa acaaccaaat ggaaaataaa cataaggtaa cagtgtgtgc 1380 tca 1383 20 311 PRT Homo sapiens 20 Met Glu Arg Pro Gln Ser Asp Phe Asn Gln Thr Glu Val Ala Glu Phe 1 5 10 15 Phe Leu Met Gly Phe Ser Asn Ser Trp Asp Ile Gln Ile Val His Ala 20 25 30 Ala Leu Phe Phe Leu Val Tyr Leu Ala Ala Val Ile Gly Asn Leu Leu 35 40 45 Ile Ile Ile Leu Thr Thr Leu Asp Val His Leu Gln Thr Pro Met Tyr 50 55 60 Phe Phe Leu Arg Asn Leu Ser Phe Leu Asp Phe Cys Tyr Ile Ser Val 65 70 75 80 Thr Ile Pro Lys Ser Ile Val Ser Ser Leu Thr His Asp Thr Ser Ile 85 90 95 Ser Phe Phe Gly Cys Ala Leu Gln Ala Phe Phe Phe Met Asp Leu Ala 100 105 110 Thr Thr Glu Val Ala Ile Leu Thr Val Met Ser Tyr Asp Arg Tyr Met 115 120 125 Ala Ile Cys Arg Pro Leu His Tyr Glu Val Ile Ile Asn Gln Gly Val 130 135 140 Cys Leu Arg Met Met Ala Met Ser Trp Leu Ser Gly Val Ile Cys Gly 145 150 155 160 Phe Met His Val Ile Ala Thr Phe Ser Leu Pro Phe Cys Gly Arg Asn 165 170 175 Arg Ile Arg Gln Phe Phe Cys Asn Ile Pro Gln Leu Leu Ser Leu Leu 180 185 190 Asp Pro Lys Val Ile Thr Ile Glu Ile Gly Val Met Val Phe Gly Thr 195 200 205 Ser Leu Val Ile Ile Ser Phe Val Val Ile Thr Leu Ser Tyr Met Tyr 210 215 220 Ile Phe Ser Val Ile Met Arg Ile Pro Ser Lys Glu Gly Arg Ser Lys 225 230 235 240 Thr Phe Ser Thr Cys Ile Pro His Leu Val Val Val Thr Leu Phe Met 245 250 255 Ile Ser Gly Ser Ile Ala Tyr Val Lys Pro Ile Ser Asn Ser Pro Pro 260 265 270 Val Leu Asp Val Phe Leu Ser Ala Phe Tyr Thr Val Val Pro Pro Thr 275 280 285 Leu Asn Pro Val Ile Tyr Ser Leu Arg Asn Arg Asp Met Lys Ala Ala 290 295 300 Leu Arg Arg Gln Cys Gly Pro 305 310 21 958 DNA Homo sapiens 21 aacatggaaa gcaatcagac ctggatcaca gaagtcatcc tgttgggatt ccaggtggac 60 ccagctctgg agttgttcct ctttgggttt ttcttgctat tctacagctt aaccctgatg 120 ggaaatggga ttatcctggg gctcatctac ttggactcta gactgcacac acccatgtat 180 gtcttcctgt cacacctggc cattgtggac atgtcctatg cctcgagtac tgtccctaag 240 atgctagcaa atcttgtgat gcacaaaaaa gtcatctcct ttgctccttg catacttcag 300 acttttttgt atttggcgtt tgctattaca gagtgtctga ttttggtgat gatgtgctat 360 gatcggtatg tggcaatctg tcaccccttg caatacaccc tcattatgaa ctggagagtg 420 tgcactgtcc tggcctcaac ttgctggata tttagctttc tcttggctct ggtccatatt 480 actcttattc tgaggctgcc tttttgtggc ccacaaaaga tcaaccactt tttctgtcaa 540 atcatgtccg tattcaaatt ggcctgtgct gacactaggc tcaaccaggt ggtcctattt 600 gcgggttctg cgttcatctt agtggggccg ctctgcctgg tgctggtctc ctacttgcac 660 atcctggtgg ccatcttgag gatccagtct ggggagggcc gcagaaaggc cttctctacc 720 tgctcctccc acctctgcgt ggtggggctt ttctttggca gcgccattgt catgtacatg 780 gcccccaggt caaaccattc tcaagaacgg aggaagatcc tttccctgtt ttacagcctt 840 ttcaacccga tcctgaaccc cctcatctac agccttagga atgcagaggt gaaaggggct 900 ctaaagagag tcctttggaa acagagatca atgtgaagaa tcatttgaga tatcctga 958 22 310 PRT Homo sapiens 22 Met Glu Ser Asn Gln Thr Trp Ile Thr Glu Val Ile Leu Leu Gly Phe 1 5 10 15 Gln Val Asp Pro Ala Leu Glu Leu Phe Leu Phe Gly Phe Phe Leu Leu 20 25 30 Phe Tyr Ser Leu Thr Leu Met Gly Asn Gly Ile Ile Leu Gly Leu Ile 35 40 45 Tyr Leu Asp Ser Arg Leu His Thr Pro Met Tyr Val Phe Leu Ser His 50 55 60 Leu Ala Ile Val Asp Met Ser Tyr Ala Ser Ser Thr Val Pro Lys Met 65 70 75 80 Leu Ala Asn Leu Val Met His Lys Lys Val Ile Ser Phe Ala Pro Cys 85 90 95 Ile Leu Gln Thr Phe Leu Tyr Leu Ala Phe Ala Ile Thr Glu Cys Leu 100 105 110 Ile Leu Val Met Met Cys Tyr Asp Arg Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Gln Tyr Thr Leu Ile Met Asn Trp Arg Val Cys Thr Val Leu Ala 130 135 140 Ser Thr Cys Trp Ile Phe Ser Phe Leu Leu Ala Leu Val His Ile Thr 145 150 155 160 Leu Ile Leu Arg Leu Pro Phe Cys Gly Pro Gln Lys Ile Asn His Phe 165 170 175 Phe Cys Gln Ile Met Ser Val Phe Lys Leu Ala Cys Ala Asp Thr Arg 180 185 190 Leu Asn Gln Val Val Leu Phe Ala Gly Ser Ala Phe Ile Leu Val Gly 195 200 205 Pro Leu Cys Leu Val Leu Val Ser Tyr Leu His Ile Leu Val Ala Ile 210 215 220 Leu Arg Ile Gln Ser Gly Glu Gly Arg Arg Lys Ala Phe Ser Thr Cys 225 230 235 240 Ser Ser His Leu Cys Val Val Gly Leu Phe Phe Gly Ser Ala Ile Val 245 250 255 Met Tyr Met Ala Pro Arg Ser Asn His Ser Gln Glu Arg Arg Lys Ile 260 265 270 Leu Ser Leu Phe Tyr Ser Leu Phe Asn Pro Ile Leu Asn Pro Leu Ile 275 280 285 Tyr Ser Leu Arg Asn Ala Glu Val Lys Gly Ala Leu Lys Arg Val Leu 290 295 300 Trp Lys Gln Arg Ser Met 305 310 23 968 DNA Homo sapiens 23 agctctacta gaaatatgga gagcagaaac caatcaacag tgactgaatt tatcttcact 60 ggattccctc agcttcagga tggtagtctc ctgtacttct ttcctttact tttcatctat 120 acttttatta tcattgataa cttattaatc ttctctgctg taaggctgga cacccatctc 180 cacaacccca tgtataattt tatcagtata ttttcctttc tggagatctg gtacaccaca 240 gccaccattc ccaagatgct ctccaacctc atcagtgaaa agaaggccat ctcaatgact 300 ggctgcatct tgcagatgta tttcttccac tcacttgaaa actcagaggg gatcttgctg 360 accaccatgg ccattgacag atacgttgcc atctgcaacc ctcttcgcta tcaaatgatc 420 atgacccccc ggctctgtgc tcaactctct gcaggttcct gcctcttcgg tttccttatc 480 ctgcttcccg agattgtgat gatttccaca ctgcctttct gtgggcccaa ccaaatccat 540 cagatcttct gtgacttggt ccctgtgcta agcctggcct gtacagacac gtccatgatt 600 ctgattgagg atgtgattca tgctgtgacc atcatcatta ccttcctaat cattgccctg 660 tcctatgtaa gaattgtcac tgtgatattg aggattccct cttctgaagg gaggcaaaag 720 gctttttcta cctgtgcagg ccaccccatg gtcttcccga tattctttgg cagtgtatca 780 ctcatgtact tgcgtttcag cgacacttat ccaccagttt tggacacagc cattgcactg 840 atgtttactg tacttgctcc attcttcaat cccatcattt atagcctgag aaacaaggac 900 atgaacaatg cgattaaaaa actgttctgt cttcaaaaag tgttgaacaa gcctggaggt 960 taatacag 968 24 315 PRT Homo sapiens 24 Met Glu Ser Arg Asn Gln Ser Thr Val Thr Glu Phe Ile Phe Thr Gly 1 5 10 15 Phe Pro Gln Leu Gln Asp Gly Ser Leu Leu Tyr Phe Phe Pro Leu Leu 20 25 30 Phe Ile Tyr Thr Phe Ile Ile Ile Asp Asn Leu Leu Ile Phe Ser Ala 35 40 45 Val Arg Leu Asp Thr His Leu His Asn Pro Met Tyr Asn Phe Ile Ser 50 55 60 Ile Phe Ser Phe Leu Glu Ile Trp Tyr Thr Thr Ala Thr Ile Pro Lys 65 70 75 80 Met Leu Ser Asn Leu Ile Ser Glu Lys Lys Ala Ile Ser Met Thr Gly 85 90 95 Cys Ile Leu Gln Met Tyr Phe Phe His Ser Leu Glu Asn Ser Glu Gly 100 105 110 Ile Leu Leu Thr Thr Met Ala Ile Asp Arg Tyr Val Ala Ile Cys Asn 115 120 125 Pro Leu Arg Tyr Gln Met Ile Met Thr Pro Arg Leu Cys Ala Gln Leu 130 135 140 Ser Ala Gly Ser Cys Leu Phe Gly Phe Leu Ile Leu Leu Pro Glu Ile 145 150 155 160 Val Met Ile Ser Thr Leu Pro Phe Cys Gly Pro Asn Gln Ile His Gln 165 170 175 Ile Phe Cys Asp Leu Val Pro Val Leu Ser Leu Ala Cys Thr Asp Thr 180 185 190 Ser Met Ile Leu Ile Glu Asp Val Ile His Ala Val Thr Ile Ile Ile 195 200 205 Thr Phe Leu Ile Ile Ala Leu Ser Tyr Val Arg Ile Val Thr Val Ile 210 215 220 Leu Arg Ile Pro Ser Ser Glu Gly Arg Gln Lys Ala Phe Ser Thr Cys 225 230 235 240 Ala Gly His Pro Met Val Phe Pro Ile Phe Phe Gly Ser Val Ser Leu 245 250 255 Met Tyr Leu Arg Phe Ser Asp Thr Tyr Pro Pro Val Leu Asp Thr Ala 260 265 270 Ile Ala Leu Met Phe Thr Val Leu Ala Pro Phe Phe Asn Pro Ile Ile 275 280 285 Tyr Ser Leu Arg Asn Lys Asp Met Asn Asn Ala Ile Lys Lys Leu Phe 290 295 300 Cys Leu Gln Lys Val Leu Asn Lys Pro Gly Gly 305 310 315 25 928 DNA Homo sapiens 25 gttttctgtc atctacatca acgccatgat aggaaatgtg ctcattgtgg tcaccatcac 60 tgccagccca tcactgagat cccccatgta ctttttcctg gcctatctct cctttattga 120 tgcctgctat tcctctgtca atgcccctaa gctgatcaca gattcactct atgaaaacaa 180 gactatctta ttcaatggat gtatgactca agtctttgga gaacattttt tcagaggtgt 240 tgaggtcatc ctacttactg taatggccta tgaccactat gtggccatct gcaagccctt 300 gcactatacc accatcatga agaagcatgt ttgtagcctg ctagtgggag tgtcatgggt 360 aggaggcttt cttcatgcaa ccatacagat cctcttcatc tgtcaattac ctttctgtgg 420 tcctaatgtc atagatcact ttatgtgtga tctctacact ttgatcaatc ttgcctgcac 480 taatacccac actctaggac tcttcattgc tgccaacagt gggttcatat gcctgttaaa 540 ctgtctcttg ctcctggtct cctgcgtggt catactgtac tccttaaaga cccacagctt 600 agaggcaagg cacgaagccc tctctacctg tgtctcccac atcacagttg tcatcttatc 660 ctttataccc tgcatatttg tgtacatgag acctccagct actttaccca ttgataaagc 720 agttgctgta ttctacacta tgataacttc tatgttaaac cccttaatct acaccttgag 780 gaatgctcaa atgaaaaatg ccattaggaa attgtgtagt aggaaagcta tttcaagtgt 840 caaataaatg tgactggagc ccaacatgat tcaactgagg caagggtcaa aaggacattt 900 tgggtaatgc cagcaaagga atacttat 928 26 281 PRT Homo sapiens 26 Phe Ser Val Ile Tyr Ile Asn Ala Met Ile Gly Asn Val Leu Ile Val 1 5 10 15 Val Thr Ile Thr Ala Ser Pro Ser Leu Arg Ser Pro Met Tyr Phe Phe 20 25 30 Leu Ala Tyr Leu Ser Phe Ile Asp Ala Cys Tyr Ser Ser Val Asn Ala 35 40 45 Pro Lys Leu Ile Thr Asp Ser Leu Tyr Glu Asn Lys Thr Ile Leu Phe 50 55 60 Asn Gly Cys Met Thr Gln Val Phe Gly Glu His Phe Phe Arg Gly Val 65 70 75 80 Glu Val Ile Leu Leu Thr Val Met Ala Tyr Asp His Tyr Val Ala Ile 85 90 95 Cys Lys Pro Leu His Tyr Thr Thr Ile Met Lys Lys His Val Cys Ser 100 105 110 Leu Leu Val Gly Val Ser Trp Val Gly Gly Phe Leu His Ala Thr Ile 115 120 125 Gln Ile Leu Phe Ile Cys Gln Leu Pro Phe Cys Gly Pro Asn Val Ile 130 135 140 Asp His Phe Met Cys Asp Leu Tyr Thr Leu Ile Asn Leu Ala Cys Thr 145 150 155 160 Asn Thr His Thr Leu Gly Leu Phe Ile Ala Ala Asn Ser Gly Phe Ile 165 170 175 Cys Leu Leu Asn Cys Leu Leu Leu Leu Val Ser Cys Val Val Ile Leu 180 185 190 Tyr Ser Leu Lys Thr His Ser Leu Glu Ala Arg His Glu Ala Leu Ser 195 200 205 Thr Cys Val Ser His Ile Thr Val Val Ile Leu Ser Phe Ile Pro Cys 210 215 220 Ile Phe Val Tyr Met Arg Pro Pro Ala Thr Leu Pro Ile Asp Lys Ala 225 230 235 240 Val Ala Val Phe Tyr Thr Met Ile Thr Ser Met Leu Asn Pro Leu Ile 245 250 255 Tyr Thr Leu Arg Asn Ala Gln Met Lys Asn Ala Ile Arg Lys Leu Cys 260 265 270 Ser Arg Lys Ala Ile Ser Ser Val Lys 275 280 27 971 DNA Homo sapiens 27 caatgatgga aatagccaat gtgagttctc cagaagtctt tgtcctcctg ggcttctccg 60 cacgaccctc actagaaact gtcctcttca tagttgtctt gagtttttac atggtatcga 120 tcttgggcaa tggcatcatc attctggtct cccatacaga tgtgcacctc cacacaccta 180 tgtacttctt tcttgccaac ctctccttcc tggacatgag cttcaccacg agcattgtcc 240 cacagctcct ggctaacctc tggggaccac agaaaaccat aagctatgga gggtgtgtgg 300 tccagttcta tatctcccat tggctggggg caaccgagtg tgtcctgctg gccaccatgt 360 cctatgaccg ctacgctgcc atctgcaggc cactccatta cactgtcatt atgcatccac 420 agctttgcct tgggctagct ttggcctcct ggctgggggg tctgaccacc agcatggtgg 480 gctccacgct caccatgctc ctaccgctgt gtgggaacaa ttgcatcgac cacttctttt 540 gcgagatgcc cctcattatg caactggctt gtgtggatac cagcctcaat gagatggaga 600 tgtacctggc cagctttgtc tttgttgtcc tgcctctggg gctcatcctg gtctcttacg 660 gccacattgc ccgggccgtg ttgaagatca ggtcagcaga agggcggaga aaggcattca 720 acacctgttc ttcccacgtg gctgtggtgt ctctgtttta cgggagcatc atcttcatgt 780 atctccagcc agccaagagc acctcccatg agcagggcaa gttcatagct ctgttctaca 840 ccgtagtcac tcctgcgctg aacccagtta tttacaacct gaggaacacg gaggtgaaga 900 gcgccctccg gcacatggta ttagagaact gctgtggctc tgcaggcaag ctggcgcaaa 960 tttagagact c 971 28 320 PRT Homo sapiens 28 Met Met Glu Ile Ala Asn Val Ser Ser Pro Glu Val Phe Val Leu Leu 1 5 10 15 Gly Phe Ser Ala Arg Pro Ser Leu Glu Thr Val Leu Phe Ile Val Val 20 25 30 Leu Ser Phe Tyr Met Val Ser Ile Leu Gly Asn Gly Ile Ile Ile Leu 35 40 45 Val Ser His Thr Asp Val His Leu His Thr Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Leu Ser Phe Leu Asp Met Ser Phe Thr Thr Ser Ile Val Pro 65 70 75 80 Gln Leu Leu Ala Asn Leu Trp Gly Pro Gln Lys Thr Ile Ser Tyr Gly 85 90 95 Gly Cys Val Val Gln Phe Tyr Ile Ser His Trp Leu Gly Ala Thr Glu 100 105 110 Cys Val Leu Leu Ala Thr Met Ser Tyr Asp Arg Tyr Ala Ala Ile Cys 115 120 125 Arg Pro Leu His Tyr Thr Val Ile Met His Pro Gln Leu Cys Leu Gly 130 135 140 Leu Ala Leu Ala Ser Trp Leu Gly Gly Leu Thr Thr Ser Met Val Gly 145 150 155 160 Ser Thr Leu Thr Met Leu Leu Pro Leu Cys Gly Asn Asn Cys Ile Asp 165 170 175 His Phe Phe Cys Glu Met Pro Leu Ile Met Gln Leu Ala Cys Val Asp 180 185 190 Thr Ser Leu Asn Glu Met Glu Met Tyr Leu Ala Ser Phe Val Phe Val 195 200 205 Val Leu Pro Leu Gly Leu Ile Leu Val Ser Tyr Gly His Ile Ala Arg 210 215 220 Ala Val Leu Lys Ile Arg Ser Ala Glu Gly Arg Arg Lys Ala Phe Asn 225 230 235 240 Thr Cys Ser Ser His Val Ala Val Val Ser Leu Phe Tyr Gly Ser Ile 245 250 255 Ile Phe Met Tyr Leu Gln Pro Ala Lys Ser Thr Ser His Glu Gln Gly 260 265 270 Lys Phe Ile Ala Leu Phe Tyr Thr Val Val Thr Pro Ala Leu Asn Pro 275 280 285 Val Ile Tyr Asn Leu Arg Asn Thr Glu Val Lys Ser Ala Leu Arg His 290 295 300 Met Val Leu Glu Asn Cys Cys Gly Ser Ala Gly Lys Leu Ala Gln Ile 305 310 315 320 29 958 DNA Homo sapiens 29 ctatggagca gagcaattat tccgtgtatg ccgactttat ccttctgggt ttgttcagca 60 acgcccgttt cccctggctt ctctttgccc tcattctcct ggtctttgtg acctccatag 120 ccagcaacgt ggtcaagatc attctcatcc acatagactc ccgcctccac acccccatgt 180 acttcctgct cagccagctc tccctcaggg acatcttgta tatttccacc attgtgccca 240 aaatgctggt cgaccaggtg atgagccaga gagccatttc ctttgcagga tgcactgccc 300 aacacttcct ctacttgacc ttagcagggg ctgagttctt cctcctagga ctcatgtcct 360 gtgatcgcta cgtagccatc tgcaaccctc tgcactatcc tgacctcatg agccgcaaga 420 tctgctggtt gattgtggcg gcagcctggc tgggagggtc tatcgatggt ttcttgctca 480 cccccgtcac catgcagttc cccttctgtg cctctcggga gatcaaccac ttcttctgcg 540 aggtgcctgc ccttctgaag ctctcctgca cggacacatc agcctacgag acagccatgt 600 atgtctgctg tattatgatg ctcctcatcc ctttctctgt gatctcgggc tcttacacaa 660 gaattctcat tactgtttat aggatgagcg aggcagaggg gaggcgaaag gctgtggcca 720 cctgctcctc acacatggtg gttgtcagcc tcttctatgg ggctgccatg tacacatacg 780 tgctgcctca ttcttaccac acccctgagc aggacaaagc tgtatctgcc ttctacacca 840 tcctcactcc catgctcaat ccactcattt acagccttag gaacaaggat gtcacggggg 900 ccctacagaa ggttgttggg aggtgtgtgt cctcaggaaa ggtaaccact ttctaaac 958 30 317 PRT Homo sapiens 30 Met Glu Gln Ser Asn Tyr Ser Val Tyr Ala Asp Phe Ile Leu Leu Gly 1 5 10 15 Leu Phe Ser Asn Ala Arg Phe Pro Trp Leu Leu Phe Ala Leu Ile Leu 20 25 30 Leu Val Phe Val Thr Ser Ile Ala Ser Asn Val Val Lys Ile Ile Leu 35 40 45 Ile His Ile Asp Ser Arg Leu His Thr Pro Met Tyr Phe Leu Leu Ser 50 55 60 Gln Leu Ser Leu Arg Asp Ile Leu Tyr Ile Ser Thr Ile Val Pro Lys 65 70 75 80 Met Leu Val Asp Gln Val Met Ser Gln Arg Ala Ile Ser Phe Ala Gly 85 90 95 Cys Thr Ala Gln His Phe Leu Tyr Leu Thr Leu Ala Gly Ala Glu Phe 100 105 110 Phe Leu Leu Gly Leu Met Ser Cys Asp Arg Tyr Val Ala Ile Cys Asn 115 120 125 Pro Leu His Tyr Pro Asp Leu Met Ser Arg Lys Ile Cys Trp Leu Ile 130 135 140 Val Ala Ala Ala Trp Leu Gly Gly Ser Ile Asp Gly Phe Leu Leu Thr 145 150 155 160 Pro Val Thr Met Gln Phe Pro Phe Cys Ala Ser Arg Glu Ile Asn His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Thr Asp Thr 180 185 190 Ser Ala Tyr Glu Thr Ala Met Tyr Val Cys Cys Ile Met Met Leu Leu 195 200 205 Ile Pro Phe Ser Val Ile Ser Gly Ser Tyr Thr Arg Ile Leu Ile Thr 210 215 220 Val Tyr Arg Met Ser Glu Ala Glu Gly Arg Arg Lys Ala Val Ala Thr 225 230 235 240 Cys Ser Ser His Met Val Val Val Ser Leu Phe Tyr Gly Ala Ala Met 245 250 255 Tyr Thr Tyr Val Leu Pro His Ser Tyr His Thr Pro Glu Gln Asp Lys 260 265 270 Ala Val Ser Ala Phe Tyr Thr Ile Leu Thr Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Asp Val Thr Gly Ala Leu Gln Lys Val 290 295 300 Val Gly Arg Cys Val Ser Ser Gly Lys Val Thr Thr Phe 305 310 315 31 1013 DNA Homo sapiens 31 cctatgtgat gtgttatctt tctcagctat gcctcagcct tggggaacac actttacata 60 tggggatggt gagacatacc aatgagagca acctagcagg tttcatcctt ttagggtttt 120 ctgattatcc tcagttacag aaggttctat ttgtgctcat attgattctg tatttactaa 180 ctattttggg gaataccacc atcattctgg tttctcgtct ggaacccaag cctcatatgc 240 cgatgtattt cttcctttct catctctcct tcctgtaccg ctgcttcacc agcagtgtta 300 ttccccagct cctggtaaac ctgtgggaac ccatgaaaac tatcgcctat ggtggctgtt 360 tggttcacct ttacaactcc catgccctgg gatccactga gtgcgtcctc ccggctctga 420 tgtcctgtga ccgctatgtg gctgtctgcc gtcctctcca ttacactgtc ttaatgcata 480 tccatctctg catggccttg gcatctatgg catggctcag tggaatagcc accaccctgg 540 tacagtccac cctcaccctg cagctgccct tctgtgggca tcgccaagtg gatcatttca 600 tctgcgaggt ccctgtgctc atcaagctgg cttgtgtggg caccacgttt aacgaggctg 660 agctttttgt ggctagtatc cttttcctta tagtgcctgt ctcattcatc ctggtctcct 720 ctggctacat tgcccacgca gtgttgagga ttaagtcagc taccgggaga cagaaagcat 780 tcgggacctg cttctcccac ctgacagtgg tcaccatctt ttatggaacc atcatcttca 840 tgtatctgca gccagccaag agtagatcca gggaccaggg caagtttgtt tctctcttct 900 acactgtggt aacccgcatg cttaaccctc ttatttatac cttgaggatc aaggaggtga 960 aaggggcatt aaagaaagtt ctagcaaagg ctctgggagt aaatatttta tga 1013 32 334 PRT Homo sapiens 32 Met Cys Tyr Leu Ser Gln Leu Cys Leu Ser Leu Gly Glu His Thr Leu 1 5 10 15 His Met Gly Met Val Arg His Thr Asn Glu Ser Asn Leu Ala Gly Phe 20 25 30 Ile Leu Leu Gly Phe Ser Asp Tyr Pro Gln Leu Gln Lys Val Leu Phe 35 40 45 Val Leu Ile Leu Ile Leu Tyr Leu Leu Thr Ile Leu Gly Asn Thr Thr 50 55 60 Ile Ile Leu Val Ser Arg Leu Glu Pro Lys Pro His Met Pro Met Tyr 65 70 75 80 Phe Phe Leu Ser His Leu Ser Phe Leu Tyr Arg Cys Phe Thr Ser Ser 85 90 95 Val Ile Pro Gln Leu Leu Val Asn Leu Trp Glu Pro Met Lys Thr Ile 100 105 110 Ala Tyr Gly Gly Cys Leu Val His Leu Tyr Asn Ser His Ala Leu Gly 115 120 125 Ser Thr Glu Cys Val Leu Pro Ala Leu Met Ser Cys Asp Arg Tyr Val 130 135 140 Ala Val Cys Arg Pro Leu His Tyr Thr Val Leu Met His Ile His Leu 145 150 155 160 Cys Met Ala Leu Ala Ser Met Ala Trp Leu Ser Gly Ile Ala Thr Thr 165 170 175 Leu Val Gln Ser Thr Leu Thr Leu Gln Leu Pro Phe Cys Gly His Arg 180 185 190 Gln Val Asp His Phe Ile Cys Glu Val Pro Val Leu Ile Lys Leu Ala 195 200 205 Cys Val Gly Thr Thr Phe Asn Glu Ala Glu Leu Phe Val Ala Ser Ile 210 215 220 Leu Phe Leu Ile Val Pro Val Ser Phe Ile Leu Val Ser Ser Gly Tyr 225 230 235 240 Ile Ala His Ala Val Leu Arg Ile Lys Ser Ala Thr Gly Arg Gln Lys 245 250 255 Ala Phe Gly Thr Cys Phe Ser His Leu Thr Val Val Thr Ile Phe Tyr 260 265 270 Gly Thr Ile Ile Phe Met Tyr Leu Gln Pro Ala Lys Ser Arg Ser Arg 275 280 285 Asp Gln Gly Lys Phe Val Ser Leu Phe Tyr Thr Val Val Thr Arg Met 290 295 300 Leu Asn Pro Leu Ile Tyr Thr Leu Arg Ile Lys Glu Val Lys Gly Ala 305 310 315 320 Leu Lys Lys Val Leu Ala Lys Ala Leu Gly Val Asn Ile Leu 325 330 33 996 DNA Homo sapiens 33 catgctggac tatgccctct ccatttacag gtagctctac tagaaatatg gagagcagaa 60 accaatcaac agtgactgaa tttatcttca ctggattccc tcagcttcag gatggtagtc 120 tcctgtactt ctttccttta cttttcatct atacttttat tatcattgat aacttattaa 180 tcttctctgc tgtaaggctg gacacccatc tccacaaccc catgtataat tttatcagta 240 tattttcctt tctggagatc tggtacacca cagccaccat tcccaagatg ctctccaacc 300 tcatcagtga aaagaaggcc atctcaatga ctggctgcat cttgcagatg tatttcttcc 360 actcacttga aaactcagag gggatcttgc tgaccaccat ggccattgac agatacgttg 420 ccatctgcaa ccctcttcgc tatcaaatga tcatgacccc ccggctctgt gctcaactct 480 ctgcaggttc ctgcctcttc ggtttcctta tcctgcttcc cgagattgtg atgatttcca 540 cactgccttt ctgtgggccc aaccaaatcc atcagatctt ctgtgacttg gtccctgtgc 600 taagcctggc ctgtacagac acgtccatga ttctgattga ggatgtgatt catgctgtga 660 ccatcatcat taccttccta atcattgccc tgtcctatgt aagaattgtc actgtgatat 720 tgaggattcc ctcttctgaa gggaggcaaa aggctttttc tacctgtgca ggccacctca 780 tggtcttccc gatattcttt ggcagtgtat cactcatgta cttgcgtttc agcgacactt 840 atccaccagt tttggacaca gccattgcac tgatgtttac tgtacttgct ccattcttca 900 atcccatcat ttatagcctg agaaacaagg acatgaacaa tgcgattaaa aaactgttct 960 gtcttcaaaa agtgttgaac aagcctggag gttaat 996 34 327 PRT Homo sapiens 34 Met Pro Ser Pro Phe Thr Gly Ser Ser Thr Arg Asn Met Glu Ser Arg 1 5 10 15 Asn Gln Ser Thr Val Thr Glu Phe Ile Phe Thr Gly Phe Pro Gln Leu 20 25 30 Gln Asp Gly Ser Leu Leu Tyr Phe Phe Pro Leu Leu Phe Ile Tyr Thr 35 40 45 Phe Ile Ile Ile Asp Asn Leu Leu Ile Phe Ser Ala Val Arg Leu Asp 50 55 60 Thr His Leu His Asn Pro Met Tyr Asn Phe Ile Ser Ile Phe Ser Phe 65 70 75 80 Leu Glu Ile Trp Tyr Thr Thr Ala Thr Ile Pro Lys Met Leu Ser Asn 85 90 95 Leu Ile Ser Glu Lys Lys Ala Ile Ser Met Thr Gly Cys Ile Leu Gln 100 105 110 Met Tyr Phe Phe His Ser Leu Glu Asn Ser Glu Gly Ile Leu Leu Thr 115 120 125 Thr Met Ala Ile Asp Arg Tyr Val Ala Ile Cys Asn Pro Leu Arg Tyr 130 135 140 Gln Met Ile Met Thr Pro Arg Leu Cys Ala Gln Leu Ser Ala Gly Ser 145 150 155 160 Cys Leu Phe Gly Phe Leu Ile Leu Leu Pro Glu Ile Val Met Ile Ser 165 170 175 Thr Leu Pro Phe Cys Gly Pro Asn Gln Ile His Gln Ile Phe Cys Asp 180 185 190 Leu Val Pro Val Leu Ser Leu Ala Cys Thr Asp Thr Ser Met Ile Leu 195 200 205 Ile Glu Asp Val Ile His Ala Val Thr Ile Ile Ile Thr Phe Leu Ile 210 215 220 Ile Ala Leu Ser Tyr Val Arg Ile Val Thr Val Ile Leu Arg Ile Pro 225 230 235 240 Ser Ser Glu Gly Arg Gln Lys Ala Phe Ser Thr Cys Ala Gly His Leu 245 250 255 Met Val Phe Pro Ile Phe Phe Gly Ser Val Ser Leu Met Tyr Leu Arg 260 265 270 Phe Ser Asp Thr Tyr Pro Pro Val Leu Asp Thr Ala Ile Ala Leu Met 275 280 285 Phe Thr Val Leu Ala Pro Phe Phe Asn Pro Ile Ile Tyr Ser Leu Arg 290 295 300 Asn Lys Asp Met Asn Asn Ala Ile Lys Lys Leu Phe Cys Leu Gln Lys 305 310 315 320 Val Leu Asn Lys Pro Gly Gly 325 35 321 PRT Mus musculus 35 Met Asn Ser Lys Ala Ser Met Leu Gly Thr Asn Phe Thr Ile Ile His 1 5 10 15 Pro Thr Val Phe Ile Leu Leu Gly Ile Pro Gly Leu Glu Gln Tyr His 20 25 30 Thr Trp Leu Ser Ile Pro Phe Cys Leu Met Tyr Ile Ala Ala Val Leu 35 40 45 Gly Asn Gly Ala Leu Ile Leu Val Val Leu Ser Glu Arg Thr Leu His 50 55 60 Glu Pro Met Tyr Val Phe Leu Ser Met Leu Ala Gly Thr Asp Ile Leu 65 70 75 80 Leu Ser Thr Thr Thr Val Pro Lys Thr Leu Ala Ile Phe Trp Phe His 85 90 95 Ala Gly Glu Ile Pro Phe Asp Ala Cys Ile Ala Gln Met Phe Phe Ile 100 105 110 His Val Ala Phe Val Ala Glu Ser Gly Ile Leu Leu Ala Met Ala Phe 115 120 125 Asp Arg Tyr Val Ala Ile Cys Thr Pro Leu Arg Tyr Ser Ala Val Leu 130 135 140 Thr Pro Met Ala Ile Gly Lys Met Thr Leu Ala Ile Trp Gly Arg Ser 145 150 155 160 Ile Gly Thr Ile Phe Pro Ile Ile Phe Leu Leu Lys Arg Leu Ser Tyr 165 170 175 Cys Arg Thr Asn Val Ile Pro His Ser Tyr Cys Glu His Ile Gly Val 180 185 190 Ala Arg Leu Ala Cys Ala Asp Ile Thr Val Asn Ile Trp Tyr Gly Phe 195 200 205 Ser Val Pro Met Ala Ser Val Leu Val Asp Val Ala Leu Ile Gly Ile 210 215 220 Ser Tyr Thr Leu Ile Leu Gln Ala Val Phe Arg Leu Pro Ser Gln Asp 225 230 235 240 Ala Arg His Lys Ala Leu Asn Thr Cys Gly Ser His Ile Gly Val Ile 245 250 255 Leu Leu Phe Phe Ile Pro Ser Phe Phe Thr Phe Leu Thr His Arg Phe 260 265 270 Gly Lys Asn Ile Pro His His Val His Ile Leu Leu Ala Asn Leu Tyr 275 280 285 Val Leu Val Pro Pro Met Leu Asn Pro Ile Ile Tyr Gly Ala Lys Thr 290 295 300 Lys Gln Ile Arg Asp Ser Met Thr Arg Met Leu Ser Val Val Trp Lys 305 310 315 320 Ser 36 326 PRT Mus musculus 36 Met Lys Val Ala Ser Ser Phe His Asn Asp Thr Asn Pro Gln Asp Val 1 5 10 15 Trp Tyr Val Leu Ile Gly Ile Pro Gly Leu Glu Asp Leu His Ser Trp 20 25 30 Ile Ala Ile Pro Ile Cys Ser Met Tyr Ile Val Ala Val Ile Gly Asn 35 40 45 Val Leu Leu Ile Phe Leu Ile Val Thr Glu Arg Ser Leu His Glu Pro 50 55 60 Met Tyr Phe Phe Leu Ser Met Leu Ala Leu Ala Asp Leu Leu Leu Ser 65 70 75 80 Thr Ala Thr Ala Pro Lys Met Leu Ala Ile Phe Trp Phe His Ser Arg 85 90 95 Gly Ile Ser Phe Gly Ser Cys Val Ser Gln Met Phe Phe Ile His Phe 100 105 110 Ile Phe Val Ala Glu Ser Ala Ile Leu Leu Ala Met Ala Phe Asp Arg 115 120 125 Tyr Val Ala Ile Cys Tyr Pro Leu Arg Tyr Thr Thr Ile Leu Thr Ser 130 135 140 Ser Val Ile Gly Lys Ile Gly Thr Ala Ala Val Val Arg Ser Phe Leu 145 150 155 160 Ile Cys Phe Pro Phe Ile Phe Leu Val Tyr Arg Leu Leu Tyr Cys Gly 165 170 175 Lys His Ile Ile Pro His Ser Tyr Cys Glu His Met Gly Ile Ala Arg 180 185 190 Leu Ala Cys Asp Asn Ile Thr Val Asn Ile Ile Tyr Gly Leu Thr Met 195 200 205 Ala Leu Leu Ser Thr Gly Leu Asp Ile Leu Leu Ile Ile Ile Ser Tyr 210 215 220 Thr Met Ile Leu Arg Thr Val Phe Gln Ile Pro Ser Trp Ala Ala Arg 225 230 235 240 Tyr Lys Ala Leu Asn Thr Cys Gly Ser His Ile Cys Val Ile Leu Leu 245 250 255 Phe Tyr Thr Pro Ala Phe Phe Ser Phe Phe Ala His Arg Phe Gly Gly 260 265 270 Lys Thr Val Pro Arg His Ile His Ile Leu Val Ala Asn Leu Tyr Val 275 280 285 Val Val Pro Pro Met Leu Asn Pro Ile Ile Tyr Gly Val Lys Thr Lys 290 295 300 Gln Ile Gln Asp Arg Val Val Phe Leu Phe Ser Ser Val Ser Thr Cys 305 310 315 320 Gln His Asp Ser Arg Cys 325 37 318 PRT Mus musculus VARIANT (286) Where Xaa is Thr, Leu, Gln or Arg 37 Met Ser Pro Gly Asn Ser Ser Trp Ile His Pro Ser Ser Phe Leu Leu 1 5 10 15 Leu Gly Ile Pro Gly Leu Glu Glu Leu Gln Phe Trp Leu Gly Leu Pro 20 25 30 Phe Gly Thr Val Tyr Leu Ile Ala Val Leu Gly Asn Val Ile Ile Leu 35 40 45 Phe Val Ile Tyr Leu Glu His Ser Leu His Gln Pro Met Phe Tyr Leu 50 55 60 Leu Ala Ile Leu Ala Val Thr Asp Leu Gly Leu Ser Thr Ala Thr Val 65 70 75 80 Pro Arg Ala Leu Gly Ile Phe Trp Phe Gly Phe His Lys Ile Ala Phe 85 90 95 Arg Asp Cys Val Ala Gln Met Phe Phe Ile His Leu Phe Thr Gly Ile 100 105 110 Glu Thr Phe Met Leu Val Ala Met Ala Phe Asp Arg Tyr Ile Ala Ile 115 120 125 Cys Asn Pro Leu Arg Tyr Asn Thr Ile Leu Thr Asn Arg Thr Ile Cys 130 135 140 Ile Ile Val Gly Val Gly Leu Phe Lys Asn Phe Ile Leu Val Phe Pro 145 150 155 160 Leu Ile Phe Leu Ile Leu Arg Leu Ser Phe Cys Gly His Asn Ile Ile 165 170 175 Pro His Thr Tyr Cys Glu His Met Gly Ile Ala Arg Leu Ala Cys Val 180 185 190 Ser Ile Lys Val Asn Val Leu Phe Gly Leu Ile Leu Ile Ser Met Ile 195 200 205 Leu Leu Asp Val Val Leu Ser Ala Leu Ser Tyr Ala Lys Ile Leu His 210 215 220 Ala Val Phe Lys Leu Pro Ser Trp Glu Ala Arg Leu Lys Ala Leu Asn 225 230 235 240 Thr Cys Gly Ser His Val Cys Val Ile Leu Ala Phe Phe Thr Pro Ala 245 250 255 Phe Phe Ser Phe Leu Thr His Arg Phe Gly His Asn Ile Pro Arg Tyr 260 265 270 Ile His Ile Leu Leu Ala Asn Leu Tyr Val Ile Ile Pro Xaa Ala Leu 275 280 285 Asn Pro Ile Ile Tyr Gly Val Arg Thr Lys Gln Ile Gln Asp Arg Ala 290 295 300 Val Thr Ile Leu Cys Asn Glu Val Gly Gln Leu Ala Asp Asp 305 310 315 38 318 PRT Homo sapiens 38 Met Ser Asp Ser Asn Leu Ser Asp Asn His Leu Pro Asp Thr Phe Phe 1 5 10 15 Leu Thr Gly Ile Pro Gly Leu Glu Ala Ala His Phe Trp Ile Ala Ile 20 25 30 Pro Phe Cys Ala Met Tyr Leu Val Ala Leu Val Gly Asn Ala Ala Leu 35 40 45 Ile Leu Val Ile Ala Met Asp Asn Ala Leu His Ala Pro Met Tyr Leu 50 55 60 Phe Leu Cys Leu Leu Ser Leu Thr Asp Leu Ala Leu Ser Ser Thr Thr 65 70 75 80 Val Pro Lys Met Leu Ala Ile Leu Trp Leu His Ala Gly Glu Ile Ser 85 90 95 Phe Gly Gly Cys Leu Ala Gln Met Phe Cys Val His Ser Ile Tyr Ala 100 105 110 Leu Glu Ser Ser Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala 115 120 125 Ile Cys Asn Pro Leu Arg Tyr Thr Thr Ile Leu Asn His Ala Val Ile 130 135 140 Gly Arg Ile Gly Phe Val Gly Leu Phe Arg Ser Val Ala Ile Val Ser 145 150 155 160 Pro Phe Ile Phe Leu Leu Arg Arg Leu Pro Tyr Cys Gly His Arg Val 165 170 175 Met Thr His Thr Tyr Cys Glu His Met Gly Ile Ala Arg Leu Ala Cys 180 185 190 Ala Asn Ile Thr Val Asn Ile Val Tyr Gly Leu Thr Val Ala Leu Leu 195 200 205 Ala Met Gly Leu Asp Ser Ile Leu Ile Ala Ile Ser Tyr Gly Phe Ile 210 215 220 Leu His Ala Val Phe His Leu Pro Ser His Asp Ala Gln His Lys Ala 225 230 235 240 Leu Ser Thr Cys Gly Ser His Ile Gly Ile Ile Leu Val Phe Tyr Ile 245 250 255 Pro Ala Phe Phe Ser Phe Leu Thr His Arg Phe Gly His His Glu Val 260 265 270 Pro Lys His Val His Ile Phe Leu Ala Asn Leu Tyr Val Leu Val Pro 275 280 285 Pro Val Leu Asn Pro Ile Leu Tyr Gly Ala Arg Thr Lys Glu Ile Arg 290 295 300 Ser Arg Leu Leu Lys Leu Leu His Leu Gly Lys Thr Ser Ile 305 310 315 39 339 PRT Mus musculus 39 Met Pro Glu Lys Met Leu Ser Lys Leu Ile Ala Tyr Leu Leu Leu Ile 1 5 10 15 Glu Ser Cys Arg Gln Thr Ala Gln Leu Val Lys Gly Arg Arg Ile Trp 20 25 30 Val Asp Ser Arg Pro His Trp Pro Asn Thr Thr His Tyr Arg Glu Leu 35 40 45 Glu Asp Gln His Val Trp Ile Ala Ile Pro Phe Cys Ser Met Tyr Ile 50 55 60 Leu Ala Leu Val Gly Asn Gly Thr Ile Leu Tyr Ile Ile Ile Thr Asp 65 70 75 80 Arg Ala Leu His Glu Pro Met Tyr Leu Phe Leu Cys Leu Leu Ser Ile 85 90 95 Thr Asp Leu Val Leu Cys Ser Thr Thr Leu Pro Lys Met Leu Ala Ile 100 105 110 Phe Trp Leu Arg Ser His Val Ile Ser Tyr His Gly Cys Leu Thr Gln 115 120 125 Met Phe Phe Val His Ala Val Phe Ala Thr Glu Ser Ala Val Leu Leu 130 135 140 Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys Arg Pro Leu His Tyr 145 150 155 160 Thr Ser Ile Leu Asn Ala Val Val Ile Gly Lys Ile Gly Leu Ala Cys 165 170 175 Val Thr Arg Gly Leu Leu Phe Val Phe Pro Phe Val Ile Leu Ile Glu 180 185 190 Arg Leu Pro Phe Cys Gly His His Ile Ile Pro His Thr Tyr Cys Glu 195 200 205 His Met Gly Ile Ala Lys Leu Ala Cys Ala Ser Ile Lys Pro Asn Thr 210 215 220 Ile Tyr Gly Leu Thr Val Ala Leu Ser Val Thr Gly Met Asp Val Val 225 230 235 240 Leu Ile Ala Thr Ser Tyr Ile Leu Ile Leu Gln Ala Val Leu Arg Leu 245 250 255 Pro Ser Lys Asp Ala Gln Phe Arg Ala Phe Ser Thr Cys Gly Ala His 260 265 270 Ile Cys Val Ile Leu Val Phe Tyr Ile Pro Ala Phe Phe Ser Phe Phe 275 280 285 Thr His Arg Phe Gly His His Val Pro Pro Gln Val His Ile Ile Leu 290 295 300 Ala Asn Leu Tyr Leu Leu Val Pro Pro Val Leu Asn Pro Leu Val Tyr 305 310 315 320 Gly Ile Asn Thr Lys Gln Ile Arg Leu Arg Ile Leu Asp Phe Phe Val 325 330 335 Lys Arg Arg 40 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 40 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 41 320 PRT Homo sapiens 41 Met Ser Ser Cys Asn Phe Thr His Ala Thr Phe Val Leu Ile Gly Ile 1 5 10 15 Pro Gly Leu Glu Lys Ala His Phe Trp Val Gly Phe Pro Leu Leu Ser 20 25 30 Met Tyr Val Val Ala Met Phe Gly Asn Cys Ile Val Val Phe Ile Val 35 40 45 Arg Thr Glu Arg Ser Leu His Ala Pro Met Tyr Leu Phe Leu Cys Met 50 55 60 Leu Ala Ala Ile Asp Leu Ala Leu Ser Thr Ser Thr Met Pro Lys Ile 65 70 75 80 Leu Ala Leu Phe Trp Phe Asp Ser Arg Glu Ile Ser Phe Glu Ala Cys 85 90 95 Leu Thr Gln Met Phe Phe Ile His Ala Leu Ser Ala Ile Glu Ser Thr 100 105 110 Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg His Ala Ala Val Leu Asn Asn Thr Val Thr Ala Gln Ile Gly 130 135 140 Ile Val Ala Val Val Arg Gly Ser Leu Phe Phe Phe Pro Leu Pro Leu 145 150 155 160 Leu Ile Lys Arg Leu Ala Phe Cys His Ser Asn Val Leu Ser His Ser 165 170 175 Tyr Cys Val His Gln Asp Val Met Lys Leu Ala Tyr Ala Asp Thr Leu 180 185 190 Pro Asn Val Val Tyr Gly Leu Thr Ala Ile Leu Leu Val Met Gly Val 195 200 205 Asp Val Met Phe Ile Ser Leu Ser Tyr Phe Leu Ile Ile Arg Thr Val 210 215 220 Leu Gln Leu Pro Ser Lys Ser Glu Arg Ala Lys Ala Phe Gly Thr Cys 225 230 235 240 Val Ser His Ile Gly Val Val Leu Ala Phe Tyr Val Pro Leu Ile Gly 245 250 255 Leu Ser Val Val His Arg Phe Gly Asn Ser Leu His Pro Ile Val Arg 260 265 270 Val Val Met Gly Asp Ile Tyr Leu Leu Leu Pro Pro Val Ile Asn Pro 275 280 285 Ile Ile Tyr Gly Ala Lys Thr Lys Gln Ile Arg Thr Arg Val Leu Ala 290 295 300 Met Phe Lys Ile Ser Cys Asp Lys Asp Leu Gln Ala Val Gly Gly Lys 305 310 315 320 42 320 PRT Mus musculus 42 Met Ser Ser Cys Asn Phe Thr His Ala Thr Phe Leu Leu Ile Gly Ile 1 5 10 15 Pro Gly Leu Glu Glu Ala His Phe Trp Phe Gly Phe Pro Leu Leu Ser 20 25 30 Met Tyr Ala Val Ala Leu Phe Gly Asn Cys Ile Val Val Phe Ile Val 35 40 45 Arg Thr Glu Arg Ser Leu His Ala Pro Met Tyr Leu Phe Leu Cys Met 50 55 60 Leu Ala Ala Ile Asp Leu Ala Leu Ser Thr Ser Thr Met Pro Lys Ile 65 70 75 80 Leu Ala Leu Phe Trp Phe Asp Ser Arg Glu Ile Thr Phe Asp Ala Cys 85 90 95 Leu Ala Gln Met Phe Phe Ile His Thr Leu Ser Ala Ile Glu Ser Thr 100 105 110 Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg His Ala Ala Val Leu Asn Asn Thr Val Thr Val Gln Ile Gly 130 135 140 Met Val Ala Leu Val Arg Gly Ser Leu Phe Phe Phe Pro Leu Pro Leu 145 150 155 160 Leu Ile Lys Arg Leu Ala Phe Cys His Ser Asn Val Leu Ser His Ser 165 170 175 Tyr Cys Val His Gln Asp Val Met Lys Leu Ala Tyr Thr Asp Thr Leu 180 185 190 Pro Asn Val Val Tyr Gly Leu Thr Ala Ile Leu Leu Val Met Gly Val 195 200 205 Asp Val Met Phe Ile Ser Leu Ser Tyr Phe Leu Ile Ile Arg Thr Val 210 215 220 Leu Gln Leu Pro Ser Lys Ser Glu Arg Ala Lys Ala Phe Gly Thr Cys 225 230 235 240 Val Ser His Ile Ser Val Val Leu Ala Phe Tyr Val Pro Leu Ile Gly 245 250 255 Leu Ser Val Val His Arg Phe Gly Asn Ser Leu Asp Pro Ile Val His 260 265 270 Val Leu Met Gly Asp Val Tyr Leu Leu Leu Pro Pro Val Ile Asn Pro 275 280 285 Ile Ile Tyr Gly Ala Lys Thr Lys Gln Ile Arg Thr Arg Val Leu Ala 290 295 300 Met Phe Lys Ile Ser Cys Asp Lys Asp Ile Glu Ala Gly Gly Asn Thr 305 310 315 320 43 319 PRT Mus musculus 43 Met Ala Thr Ser Asn Ser Ser Thr Ile Val Ser Ser Thr Phe Tyr Leu 1 5 10 15 Thr Gly Ile Pro Gly Tyr Glu Glu Phe His His Trp Ile Ser Ile Pro 20 25 30 Phe Cys Phe Leu Tyr Leu Val Gly Ile Thr Gly Asn Cys Met Ile Leu 35 40 45 His Ile Val Arg Thr Asp Pro Arg Leu His Glu Pro Met Tyr Tyr Phe 50 55 60 Leu Ala Met Leu Ser Leu Thr Asp Met Ala Met Ser Leu Pro Thr Met 65 70 75 80 Met Ser Leu Phe Arg Val Leu Trp Ser Ile Ser Arg Glu Ile Gln Phe 85 90 95 Asn Ile Cys Val Val Gln Met Phe Leu Ile His Thr Phe Ser Phe Thr 100 105 110 Glu Ser Ser Val Leu Leu Ala Met Ala Leu Asp Arg Tyr Val Ala Ile 115 120 125 Cys His Pro Leu Arg Tyr Ala Thr Ile Leu Thr Pro Lys Leu Ile Ala 130 135 140 Lys Ile Gly Thr Ala Ala Leu Leu Arg Ser Ser Ile Leu Ile Ile Pro 145 150 155 160 Leu Ile Ala Arg Leu Ala Phe Phe Pro Phe Cys Gly Ser His Val Leu 165 170 175 Ser His Ser Tyr Cys Leu His Gln Asp Met Ile Arg Leu Ala Cys Ala 180 185 190 Asp Ile Arg Phe Asn Val Ile Tyr Gly Leu Val Leu Ile Thr Leu Leu 195 200 205 Trp Gly Met Asp Ser Leu Gly Ile Phe Val Ser Tyr Val Leu Ile Leu 210 215 220 His Ser Val Leu Lys Ile Ala Ser Arg Glu Gly Arg Leu Lys Ala Leu 225 230 235 240 Asn Thr Cys Ala Ser His Ile Cys Ala Val Leu Ile Leu Tyr Val Pro 245 250 255 Met Ile Gly Leu Ser Ile Val His Arg Phe Ala Lys His Ser Ser Pro 260 265 270 Leu Ile His Ile Phe Met Ala His Ile Tyr Leu Leu Val Pro Pro Val 275 280 285 Leu Asn Pro Ile Ile Tyr Ser Val Lys Thr Lys Gln Ile Arg Glu Gly 290 295 300 Ile Leu His Leu Leu Cys Ser Pro Lys Ile Ser Ser Ile Thr Met 305 310 315 44 320 PRT Rattus norvegicus 44 Met Ser Ser Cys Asn Phe Thr His Ala Thr Phe Met Leu Ile Gly Ile 1 5 10 15 Pro Gly Leu Glu Glu Ala His Phe Trp Phe Gly Phe Pro Leu Leu Ser 20 25 30 Met Tyr Ala Val Ala Leu Phe Gly Asn Cys Ile Val Val Phe Ile Val 35 40 45 Arg Thr Glu Arg Ser Leu His Ala Pro Met Tyr Leu Phe Leu Cys Met 50 55 60 Leu Ala Ala Ile Asp Leu Ala Leu Ser Thr Ser Thr Met Pro Lys Ile 65 70 75 80 Leu Ala Leu Phe Trp Phe Asp Ser Arg Glu Ile Thr Phe Asp Ala Cys 85 90 95 Leu Ala Gln Met Phe Phe Ile His Ala Leu Ser Ala Ile Glu Ser Thr 100 105 110 Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg His Ala Ala Val Leu Asn Asn Thr Val Thr Val Gln Ile Gly 130 135 140 Met Val Ala Leu Val Arg Gly Ser Leu Phe Phe Phe Pro Leu Pro Leu 145 150 155 160 Leu Ile Lys Arg Leu Ala Phe Cys His Ser Asn Val Leu Ser His Ser 165 170 175 Tyr Cys Val His Gln Asp Val Met Lys Leu Ala Tyr Thr Asp Thr Leu 180 185 190 Pro Asn Val Val Tyr Gly Leu Thr Ala Ile Leu Leu Val Met Gly Val 195 200 205 Asp Val Met Phe Ile Ser Leu Ser Tyr Phe Leu Ile Ile Arg Ala Val 210 215 220 Leu Gln Leu Pro Ser Lys Ser Glu Arg Ala Lys Ala Phe Gly Thr Cys 225 230 235 240 Val Ser His Ile Gly Val Val Leu Ala Phe Tyr Val Pro Leu Ile Gly 245 250 255 Leu Ser Val Val His Arg Phe Gly Asn Ser Leu Asp Pro Ile Val His 260 265 270 Val Leu Met Gly Asp Val Tyr Leu Leu Leu Pro Pro Val Ile Asn Pro 275 280 285 Ile Ile Tyr Gly Ala Lys Thr Lys Gln Ile Arg Thr Arg Val Leu Ala 290 295 300 Met Phe Lys Ile Ser Cys Asp Lys Asp Ile Glu Ala Gly Gly Asn Thr 305 310 315 320 45 312 PRT Homo sapiens 45 Met Gly Leu Phe Asn Val Thr His Pro Ala Phe Phe Leu Leu Thr Gly 1 5 10 15 Ile Pro Gly Leu Glu Ser Ser His Ser Trp Leu Ser Gly Pro Leu Cys 20 25 30 Val Met Tyr Ala Val Ala Leu Gly Gly Asn Thr Val Ile Leu Gln Ala 35 40 45 Val Arg Val Glu Pro Ser Leu His Glu Pro Met Tyr Tyr Phe Leu Ser 50 55 60 Met Leu Ser Phe Ser Asp Val Ala Ile Ser Met Ala Thr Leu Pro Thr 65 70 75 80 Val Leu Arg Thr Phe Cys Leu Asn Ala Arg Asn Ile Thr Phe Asp Ala 85 90 95 Cys Leu Ile Gln Met Phe Leu Ile His Phe Phe Ser Met Met Glu Ser 100 105 110 Gly Ile Leu Leu Ala Met Ser Phe Asp Arg Tyr Val Ala Ile Cys Asp 115 120 125 Pro Leu Arg Tyr Ala Thr Val Leu Thr Thr Glu Val Ile Ala Ala Met 130 135 140 Gly Leu Gly Ala Ala Ala Arg Ser Phe Ile Thr Leu Phe Pro Leu Pro 145 150 155 160 Phe Leu Ile Lys Arg Leu Pro Ile Cys Arg Ser Asn Val Leu Ser His 165 170 175 Ser Tyr Cys Leu His Pro Asp Met Met Arg Leu Ala Cys Ala Asp Ile 180 185 190 Ser Ile Asn Ser Ile Tyr Gly Leu Phe Val Leu Val Ser Thr Phe Gly 195 200 205 Met Asp Leu Phe Phe Ile Phe Leu Ser Tyr Val Leu Ile Leu Arg Ser 210 215 220 Val Met Ala Thr Ala Ser Arg Glu Glu Arg Leu Lys Ala Leu Asn Thr 225 230 235 240 Cys Val Ser His Ile Leu Ala Val Leu Ala Phe Tyr Val Pro Met Ile 245 250 255 Gly Val Ser Thr Val His Arg Phe Gly Lys His Val Pro Cys Tyr Ile 260 265 270 His Val Leu Met Ser Asn Val Tyr Leu Phe Val Pro Pro Val Leu Asn 275 280 285 Pro Leu Ile Tyr Ser Ala Lys Thr Lys Glu Ile Arg Arg Ala Ile Phe 290 295 300 Arg Met Phe His His Ile Lys Ile 305 310 46 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 46 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 47 357 PRT Homo sapiens 47 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Gln Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu Asn Gln Glu Ile Arg Asn Met Gln Met Ile 305 310 315 320 Ser Phe Ala Lys Asp Thr Val Leu Thr Tyr Leu Thr Asn Phe Ser Ala 325 330 335 Ser Cys Pro Ile Phe Val Ile Thr Ile Glu Asn Tyr Cys Asn Leu Pro 340 345 350 Gln Arg Lys Phe Pro 355 48 357 PRT Homo sapiens 48 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Arg Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu Asn Gln Glu Ile Arg Asn Met Gln Met Ile 305 310 315 320 Ser Phe Ala Lys Asp Thr Val Leu Thr Tyr Leu Thr Asn Phe Ser Ala 325 330 335 Ser Cys Pro Ile Phe Val Ile Thr Ile Glu Asn Tyr Cys Asn Leu Pro 340 345 350 Gln Arg Lys Phe Pro 355 49 310 PRT Homo sapiens 49 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Gln Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu 305 310 50 313 PRT Rattus norvegicus 50 Met Ser Val Ala Asn Glu Ser Ile Ser Arg Glu Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asp Arg Pro Trp Leu Glu Leu Pro Leu Phe Val Val Phe Leu 20 25 30 Val Ser Tyr Ile Leu Thr Ile Phe Gly Asn Met Met Ile Ile Leu Val 35 40 45 Ser Arg Leu Asp Ser Lys Leu His Thr Pro Met Tyr Phe Phe Leu Thr 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Ile Asn Ile Cys Ser Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Val Gln Leu Phe Ile Phe Leu Ser Leu Gly Ser Thr Glu Cys 100 105 110 Phe Leu Leu Gly Val Met Ser Leu Asp Arg Phe Leu Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Val Ile Met His Gln Arg Arg Cys Leu His Leu 130 135 140 Ala Ala Ala Cys Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Gln Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Lys Ile Arg Ser Ala Glu Cys Arg Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Val Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Tyr Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Tyr Gly Ile Ile Thr Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Glu Glu Val Lys Gly Ala Phe Lys Arg Leu 290 295 300 Met Lys Arg Ile Ile Leu Ile Gly Lys 305 310 51 313 PRT Homo sapiens 51 Met Asn Trp Val Asn Asp Ser Ile Ile Gln Glu Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asp Arg Pro Trp Leu Glu Phe Pro Leu Leu Val Val Phe Leu 20 25 30 Ile Ser Tyr Thr Val Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser Arg Leu Asp Thr Lys Leu His Thr Pro Met Tyr Phe Phe Leu Thr 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Cys Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Leu Cys Ser Ile Arg Lys Val Ile Ser Tyr Arg Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ala Thr Glu Tyr 100 105 110 Leu Leu Leu Ala Val Met Ser Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Val Ile Met His Gln Arg Leu Cys Leu Gln Leu 130 135 140 Ala Ala Ala Ser Trp Val Thr Gly Phe Ser Asn Ser Val Trp Leu Ser 145 150 155 160 Thr Leu Thr Leu Gln Leu Pro Leu Cys Asp Pro Tyr Val Ile Asp His 165 170 175 Phe Leu Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Glu Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Leu Val Ser Glu Leu Phe His Leu 195 200 205 Ile Pro Leu Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Arg Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Arg Gln Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Ser Thr Ala Val 245 250 255 Ser Val Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Gln Gly Lys 260 265 270 Met Val Ser Leu Phe Tyr Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Gly Phe Lys Arg Leu 290 295 300 Val Ala Arg Val Phe Leu Ile Lys Lys 305 310 52 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 52 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 53 310 PRT Mus musculus 53 Met Thr Ala Lys Asn Ser Ser Val Thr Glu Phe Ile Leu Ala Gly Leu 1 5 10 15 Thr Asp Gln Pro Gly Leu Arg Met Pro Leu Phe Phe Leu Phe Leu Gly 20 25 30 Phe Tyr Met Val Thr Val Val Gly Asn Leu Gly Leu Ile Ser Leu Ile 35 40 45 Gly Leu Asn Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Phe Asn 50 55 60 Leu Ser Leu Ile Asp Phe Cys Tyr Ser Ser Thr Ile Ser Pro Lys Met 65 70 75 80 Leu Met Ser Phe Ile Ser Lys Lys Asn Ile Ile Ser His Pro Gly Cys 85 90 95 Met Ala Gln Leu Phe Phe Phe Cys Phe Phe Val Ile Ser Glu Ser Phe 100 105 110 Ile Leu Ser Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro 115 120 125 Leu Met Tyr Met Val Thr Met Ser Pro Gln Val Cys Leu Leu Leu Leu 130 135 140 Phe Gly Val Tyr Leu Met Gly Phe Val Gly Ala Met Ala His Thr Ile 145 150 155 160 Ser Met Ala Arg Leu Thr Phe Cys Ala Asp Asn Ile Val Asn His Tyr 165 170 175 Met Cys Asp Ile Leu Pro Leu Leu Glu His Ser Cys Thr Ser Thr Tyr 180 185 190 Val Asn Glu Leu Val Val Phe Ile Phe Val Ser Phe Asp Ile Gly Val 195 200 205 Pro Ile Val Thr Ile Phe Ile Ser Tyr Ala Leu Ile Leu Ser Ser Ile 210 215 220 Leu His Met His Ser Thr Glu Gly Arg Ser Lys Ala Phe Ser Thr Cys 225 230 235 240 Ser Ser His Met Ile Val Val Cys Leu Phe Phe Gly Ser Gly Ala Phe 245 250 255 Met Tyr Leu Gln Pro Pro Ser Val Leu Ser Leu Asp Gln Gly Lys Val 260 265 270 Ser Ser Leu Phe Tyr Thr Ile Val Val Pro Met Leu Asn Pro Leu Ile 275 280 285 Tyr Ser Leu Arg Asn Lys Asp Val Lys Val Ala Val Arg Lys Thr Leu 290 295 300 Asp Arg Arg Ile Phe Ser 305 310 54 310 PRT Mus musculus 54 Met Ala Thr Glu Asn Ala Ser Val Pro Glu Phe Ile Leu Ala Gly Leu 1 5 10 15 Thr Asp Gln Pro Gly Leu Arg Met Pro Leu Phe Phe Leu Phe Leu Gly 20 25 30 Phe Tyr Met Val Thr Met Val Gly Asn Leu Gly Leu Ile Thr Leu Ile 35 40 45 Gly Leu Asn Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Phe Asn 50 55 60 Leu Ser Leu Ile Asp Phe Cys Tyr Ser Thr Val Ile Thr Pro Lys Met 65 70 75 80 Leu Val Ser Phe Val Ser Lys Lys Asn Ile Ile Ser Tyr Ser Gly Cys 85 90 95 Met Thr Gln Leu Phe Phe Phe Leu Phe Phe Val Val Ser Glu Ser Phe 100 105 110 Ile Leu Ser Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro 115 120 125 Leu Met Tyr Thr Val Thr Met Ser Pro Gln Val Cys Leu Leu Leu Leu 130 135 140 Leu Gly Val Tyr Val Met Gly Phe Ala Gly Ala Met Ala His Thr Ala 145 150 155 160 Phe Met Val Lys Leu Thr Phe Cys Ala Asp Lys Leu Val Asn His Tyr 165 170 175 Met Cys Asp Ile Leu Pro Leu Leu Glu Arg Ser Cys Thr Ser Thr Tyr 180 185 190 Val Asn Glu Leu Val Val Phe Ile Val Val Gly Ile Asp Ile Gly Val 195 200 205 Pro Thr Val Thr Ile Phe Ile Ser Tyr Ala Leu Ile Leu Ser Ser Ile 210 215 220 Leu Arg Ile Ser Ser Thr Glu Gly Arg Ser Lys Ala Phe Ser Thr Cys 225 230 235 240 Ser Ser His Ile Ile Ala Val Ser Leu Phe Phe Gly Ser Gly Ala Phe 245 250 255 Met Tyr Leu Lys Pro Ser Ser Leu Leu Pro Met Asn Gln Gly Lys Val 260 265 270 Ser Ser Leu Phe Tyr Thr Ile Val Val Pro Met Leu Asn Pro Leu Ile 275 280 285 Tyr Ser Leu Arg Asn Lys Asp Val Lys Val Ala Leu Arg Lys Thr Leu 290 295 300 Ser Arg Ser Ser Phe Ser 305 310 55 309 PRT Mus musculus 55 Met Thr Ala Lys Asn Ser Ser Val Ile Glu Phe Ile Leu Ala Gly Leu 1 5 10 15 Thr Asp Gln Pro Gly Leu Arg Met Pro Leu Phe Phe Leu Phe Leu Gly 20 25 30 Phe Tyr Met Val Thr Val Val Gly Asn Leu Gly Leu Ile Ser Leu Ile 35 40 45 Gly Leu Asn Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Phe Asn 50 55 60 Leu Ser Val Ile Asp Phe Cys Tyr Ser Ser Thr Ile Ile Pro Lys Met 65 70 75 80 Leu Met Asn Phe Ile Ser Arg Lys Asn Ile Ile Ser His Ser Gly Cys 85 90 95 Met Thr Gln Leu Phe Phe Phe Cys Phe Phe Val Val Ser Glu Ser Phe 100 105 110 Ile Leu Ser Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro 115 120 125 Leu Met Tyr Thr Val Thr Met Ser Pro Gln Val Tyr Leu Leu Leu Leu 130 135 140 Leu Gly Val Tyr Val Met Gly Phe Ser Gly Ala Met Ala Ile Gln Glu 145 150 155 160 Leu Met Asn Leu Thr Phe Cys Ala Asp Asn Leu Ile Asn His Phe Met 165 170 175 Cys Asp Ile Leu Pro Leu Leu Glu Leu Ser Cys Asn Ser Thr Phe Ile 180 185 190 Asn Glu Leu Val Ile Phe Ile Val Val Ala Phe Asp Ile Gly Val Pro 195 200 205 Ile Val Thr Ile Phe Ile Ser Tyr Ala Leu Ile Leu Ser Ser Ile Leu 210 215 220 Arg Met His Ser Thr Glu Gly Arg Ser Lys Ala Phe Ser Thr Tyr Ser 225 230 235 240 Ser His Leu Ile Val Val Cys Leu Phe Phe Gly Ser Gly Ala Phe Met 245 250 255 Tyr Leu Lys Pro Pro Ser Ile Leu Pro Leu Asp Gln Gly Lys Val Ser 260 265 270 Ser Leu Phe Tyr Met Ile Val Val Pro Met Leu Asn Pro Leu Ile Tyr 275 280 285 Ser Leu Arg Asn Lys Asp Val Lys Val Gly Leu Arg Lys Thr Leu Gly 290 295 300 Lys Arg Ile Leu Ser 305 56 304 PRT Rattus norvegicus 56 Ser Val Thr Glu Phe Ile Leu Ala Gly Leu Thr Asp Gln Pro Gly Leu 1 5 10 15 Arg Met Pro Leu Phe Phe Leu Phe Leu Gly Phe Tyr Met Val Thr Val 20 25 30 Val Gly Asn Leu Ile Gly Leu Phe Leu Ile Gly Leu Asn Ser His Leu 35 40 45 His Thr Pro Met Tyr Phe Phe Leu Phe Asn Leu Ser Val Val Asp Phe 50 55 60 Cys Phe Ser Ser Thr Ile Ile Pro Lys Met Leu Met Ser Phe Ile Ser 65 70 75 80 Lys Lys Asn Ile Ile Ser His Ser Gly Cys Met Thr Gln Leu Phe Phe 85 90 95 Phe Cys Phe Phe Val Val Ser Glu Thr Phe Ile Leu Ser Ala Met Ala 100 105 110 Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro Leu Met Tyr Thr Val Thr 115 120 125 Met Ser Pro Gln Val Cys Leu Leu Leu Leu Leu Gly Ala Tyr Val Met 130 135 140 Gly Phe Ser Glu Ala Met Ala His Thr Gly Asn Leu Met Asn Leu Thr 145 150 155 160 Phe Cys Ala Asp Asn Leu Val Asn His Phe Met Cys Asp Ile Leu Pro 165 170 175 Leu Leu Glu Leu Ser Cys Asn Ser Thr Phe Ile Asn Glu Leu Val Val 180 185 190 Phe Ile Val Val Ala Ile Asp Ile Ala Val Pro Ile Val Ser Ile Phe 195 200 205 Ile Ser Tyr Ala Leu Ile Leu Ser Ser Ile Leu Arg Met His Ser Thr 210 215 220 Glu Gly Arg Ser Lys Ala Phe Ser Thr Cys Ser Ser His Leu Ile Val 225 230 235 240 Val Cys Leu Leu Phe Gly Ser Gly Ala Phe Met Tyr Leu Lys Leu Pro 245 250 255 Ser Ile Leu Pro Leu Asp Gln Gly Lys Val Ser Ser Leu Phe Tyr Thr 260 265 270 Ile Val Val Pro Met Leu Asn Pro Leu Ile Tyr Ser Leu Arg Asn Lys 275 280 285 Asp Val Lys Val Ala Leu Arg Lys Thr Leu Gly Lys Ile Ile Leu Ser 290 295 300 57 311 PRT Homo sapiens 57 Met Ala Ala Glu Asn Ser Ser Phe Val Thr Gln Phe Ile Leu Ala Gly 1 5 10 15 Leu Thr Asp Gln Pro Gly Val Gln Ile Pro Leu Phe Phe Leu Phe Leu 20 25 30 Gly Phe Tyr Val Val Thr Val Val Gly Asn Leu Gly Leu Ile Thr Leu 35 40 45 Ile Arg Leu Asn Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Tyr 50 55 60 Asn Leu Ser Phe Ile Asp Phe Cys Tyr Ser Ser Val Ile Thr Pro Lys 65 70 75 80 Met Leu Met Ser Phe Val Leu Lys Lys Asn Ser Ile Ser Tyr Ala Gly 85 90 95 Cys Met Thr Gln Leu Phe Phe Phe Leu Phe Phe Val Val Ser Glu Ser 100 105 110 Phe Ile Leu Ser Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn 115 120 125 Pro Leu Leu Tyr Met Val Thr Met Ser Pro Gln Val Cys Phe Leu Leu 130 135 140 Leu Leu Gly Val Tyr Gly Met Gly Phe Ala Gly Ala Met Ala His Thr 145 150 155 160 Ala Cys Met Met Gly Val Thr Phe Cys Ala Asn Asn Leu Val Asn His 165 170 175 Tyr Met Cys Asp Ile Leu Pro Leu Leu Glu Cys Ala Cys Thr Ser Thr 180 185 190 Tyr Val Asn Glu Leu Val Val Phe Val Val Val Gly Ile Asp Ile Gly 195 200 205 Val Pro Thr Val Thr Ile Phe Ile Ser Tyr Ala Leu Ile Leu Ser Ser 210 215 220 Ile Phe His Ile Asp Ser Thr Glu Gly Arg Ser Lys Ala Phe Ser Thr 225 230 235 240 Cys Ser Ser His Ile Ile Ala Val Ser Leu Phe Phe Gly Ser Gly Ala 245 250 255 Phe Met Tyr Leu Lys Pro Phe Ser Leu Leu Ala Met Asn Gln Gly Lys 260 265 270 Val Ser Ser Leu Phe Tyr Thr Thr Val Val Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Asp Val Lys Val Ala Leu Lys Lys Ile 290 295 300 Leu Asn Lys Asn Ala Phe Ser 305 310 58 241 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 58 Lys Leu Arg Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala 1 5 10 15 Asp Leu Leu Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu 20 25 30 Val Gly Gly Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly 35 40 45 Ala Leu Phe Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala 50 55 60 Ile Ser Ile Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg 65 70 75 80 Arg Ile Arg Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp 85 90 95 Val Leu Ala Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu 100 105 110 Arg Thr Val Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro 115 120 125 Glu Glu Ser Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly 130 135 140 Phe Val Leu Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu 145 150 155 160 Arg Thr Leu Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg 165 170 175 Ser Ser Ser Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val 180 185 190 Val Phe Val Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp 195 200 205 Ser Leu Cys Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu 210 215 220 Ile Thr Leu Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile 225 230 235 240 Tyr 59 321 PRT Mus musculus 59 Met Asn Ser Lys Ala Ser Met Leu Gly Thr Asn Phe Thr Ile Ile His 1 5 10 15 Pro Thr Val Phe Ile Leu Leu Gly Ile Pro Gly Leu Glu Gln Tyr His 20 25 30 Thr Trp Leu Ser Ile Pro Phe Cys Leu Met Tyr Ile Ala Ala Val Leu 35 40 45 Gly Asn Gly Ala Leu Ile Leu Val Val Leu Ser Glu Arg Thr Leu His 50 55 60 Glu Pro Met Tyr Val Phe Leu Ser Met Leu Ala Gly Thr Asp Ile Leu 65 70 75 80 Leu Ser Thr Thr Thr Val Pro Lys Thr Leu Ala Ile Phe Trp Phe His 85 90 95 Ala Gly Glu Ile Pro Phe Asp Ala Cys Ile Ala Gln Met Phe Phe Ile 100 105 110 His Val Ala Phe Val Ala Glu Ser Gly Ile Leu Leu Ala Met Ala Phe 115 120 125 Asp Arg Tyr Val Ala Ile Cys Thr Pro Leu Arg Tyr Ser Ala Val Leu 130 135 140 Thr Pro Met Ala Ile Gly Lys Met Thr Leu Ala Ile Trp Gly Arg Ser 145 150 155 160 Ile Gly Thr Ile Phe Pro Ile Ile Phe Leu Leu Lys Arg Leu Ser Tyr 165 170 175 Cys Arg Thr Asn Val Ile Pro His Ser Tyr Cys Glu His Ile Gly Val 180 185 190 Ala Arg Leu Ala Cys Ala Asp Ile Thr Val Asn Ile Trp Tyr Gly Phe 195 200 205 Ser Val Pro Met Ala Ser Val Leu Val Asp Val Ala Leu Ile Gly Ile 210 215 220 Ser Tyr Thr Leu Ile Leu Gln Ala Val Phe Arg Leu Pro Ser Gln Asp 225 230 235 240 Ala Arg His Lys Ala Leu Asn Thr Cys Gly Ser His Ile Gly Val Ile 245 250 255 Leu Leu Phe Phe Ile Pro Ser Phe Phe Thr Phe Leu Thr His Arg Phe 260 265 270 Gly Lys Asn Ile Pro His His Val His Ile Leu Leu Ala Asn Leu Tyr 275 280 285 Val Leu Val Pro Pro Met Leu Asn Pro Ile Ile Tyr Gly Ala Lys Thr 290 295 300 Lys Gln Ile Arg Asp Ser Met Thr Arg Met Leu Ser Val Val Trp Lys 305 310 315 320 Ser 60 326 PRT Mus musculus 60 Met Lys Val Ala Ser Ser Phe His Asn Asp Thr Asn Pro Gln Asp Val 1 5 10 15 Trp Tyr Val Leu Ile Gly Ile Pro Gly Leu Glu Asp Leu His Ser Trp 20 25 30 Ile Ala Ile Pro Ile Cys Ser Met Tyr Ile Val Ala Val Ile Gly Asn 35 40 45 Val Leu Leu Ile Phe Leu Ile Val Thr Glu Arg Ser Leu His Glu Pro 50 55 60 Met Tyr Phe Phe Leu Ser Met Leu Ala Leu Ala Asp Leu Leu Leu Ser 65 70 75 80 Thr Ala Thr Ala Pro Lys Met Leu Ala Ile Phe Trp Phe His Ser Arg 85 90 95 Gly Ile Ser Phe Gly Ser Cys Val Ser Gln Met Phe Phe Ile His Phe 100 105 110 Ile Phe Val Ala Glu Ser Ala Ile Leu Leu Ala Met Ala Phe Asp Arg 115 120 125 Tyr Val Ala Ile Cys Tyr Pro Leu Arg Tyr Thr Thr Ile Leu Thr Ser 130 135 140 Ser Val Ile Gly Lys Ile Gly Thr Ala Ala Val Val Arg Ser Phe Leu 145 150 155 160 Ile Cys Phe Pro Phe Ile Phe Leu Val Tyr Arg Leu Leu Tyr Cys Gly 165 170 175 Lys His Ile Ile Pro His Ser Tyr Cys Glu His Met Gly Ile Ala Arg 180 185 190 Leu Ala Cys Asp Asn Ile Thr Val Asn Ile Ile Tyr Gly Leu Thr Met 195 200 205 Ala Leu Leu Ser Thr Gly Leu Asp Ile Leu Leu Ile Ile Ile Ser Tyr 210 215 220 Thr Met Ile Leu Arg Thr Val Phe Gln Ile Pro Ser Trp Ala Ala Arg 225 230 235 240 Tyr Lys Ala Leu Asn Thr Cys Gly Ser His Ile Cys Val Ile Leu Leu 245 250 255 Phe Tyr Thr Pro Ala Phe Phe Ser Phe Phe Ala His Arg Phe Gly Gly 260 265 270 Lys Thr Val Pro Arg His Ile His Ile Leu Val Ala Asn Leu Tyr Val 275 280 285 Val Val Pro Pro Met Leu Asn Pro Ile Ile Tyr Gly Val Lys Thr Lys 290 295 300 Gln Ile Gln Asp Arg Val Val Phe Leu Phe Ser Ser Val Ser Thr Cys 305 310 315 320 Gln His Asp Ser Arg Cys 325 61 339 PRT Mus musculus 61 Met Pro Glu Lys Met Leu Ser Lys Leu Ile Ala Tyr Leu Leu Leu Ile 1 5 10 15 Glu Ser Cys Arg Gln Thr Ala Gln Leu Val Lys Gly Arg Arg Ile Trp 20 25 30 Val Asp Ser Arg Pro His Trp Pro Asn Thr Thr His Tyr Arg Glu Leu 35 40 45 Glu Asp Gln His Val Trp Ile Ala Ile Pro Phe Cys Ser Met Tyr Ile 50 55 60 Leu Ala Leu Val Gly Asn Gly Thr Ile Leu Tyr Ile Ile Ile Thr Asp 65 70 75 80 Arg Ala Leu His Glu Pro Met Tyr Leu Phe Leu Cys Leu Leu Ser Ile 85 90 95 Thr Asp Leu Val Leu Cys Ser Thr Thr Leu Pro Lys Met Leu Ala Ile 100 105 110 Phe Trp Leu Arg Ser His Val Ile Ser Tyr His Gly Cys Leu Thr Gln 115 120 125 Met Phe Phe Val His Ala Val Phe Ala Thr Glu Ser Ala Val Leu Leu 130 135 140 Ala Met Ala Phe Asp Arg Tyr Val Ala Ile Cys Arg Pro Leu His Tyr 145 150 155 160 Thr Ser Ile Leu Asn Ala Val Val Ile Gly Lys Ile Gly Leu Ala Cys 165 170 175 Val Thr Arg Gly Leu Leu Phe Val Phe Pro Phe Val Ile Leu Ile Glu 180 185 190 Arg Leu Pro Phe Cys Gly His His Ile Ile Pro His Thr Tyr Cys Glu 195 200 205 His Met Gly Ile Ala Lys Leu Ala Cys Ala Ser Ile Lys Pro Asn Thr 210 215 220 Ile Tyr Gly Leu Thr Val Ala Leu Ser Val Thr Gly Met Asp Val Val 225 230 235 240 Leu Ile Ala Thr Ser Tyr Ile Leu Ile Leu Gln Ala Val Leu Arg Leu 245 250 255 Pro Ser Lys Asp Ala Gln Phe Arg Ala Phe Ser Thr Cys Gly Ala His 260 265 270 Ile Cys Val Ile Leu Val Phe Tyr Ile Pro Ala Phe Phe Ser Phe Phe 275 280 285 Thr His Arg Phe Gly His His Val Pro Pro Gln Val His Ile Ile Leu 290 295 300 Ala Asn Leu Tyr Leu Leu Val Pro Pro Val Leu Asn Pro Leu Val Tyr 305 310 315 320 Gly Ile Asn Thr Lys Gln Ile Arg Leu Arg Ile Leu Asp Phe Phe Val 325 330 335 Lys Arg Arg 62 269 PRT Homo sapiens 62 Met Ser Asp Ser Asn Leu Ser Asp Asn His Leu Pro Asp Thr Phe Phe 1 5 10 15 Leu Thr Gly Ile Pro Gly Leu Glu Ala Ala His Phe Trp Ile Ala Ile 20 25 30 Pro Phe Cys Ala Met Tyr Leu Val Ala Leu Val Gly Asn Ala Ala Leu 35 40 45 Ile Leu Val Ile Ala Met Asp Asn Ala Leu His Ala Pro Met Tyr Leu 50 55 60 Phe Leu Cys Leu Leu Ser Leu Thr Asp Leu Ala Leu Ser Ser Thr Thr 65 70 75 80 Val Pro Lys Met Leu Ala Ile Leu Trp Leu His Ala Gly Glu Ile Ser 85 90 95 Phe Gly Gly Cys Leu Ala Gln Met Phe Cys Val His Ser Ile Tyr Ala 100 105 110 Leu Glu Ser Ser Ile Leu Leu Ala Met Ala Phe Asp Arg Tyr Val Ala 115 120 125 Ile Cys Asn Pro Leu Arg Tyr Thr Thr Ile Leu Asn His Ala Val Ile 130 135 140 Gly Arg Ile Gly Phe Val Gly Leu Phe Arg Ser Val Ala Ile Val Ser 145 150 155 160 Pro Phe Ile Phe Leu Leu Arg Arg Leu Pro Tyr Cys Gly His Arg Val 165 170 175 Met Thr His Thr Tyr Cys Glu His Met Gly Ile Ala Arg Leu Ala Cys 180 185 190 Ala Asn Ile Thr Val Asn Ile Val Tyr Gly Leu Thr Val Ala Leu Leu 195 200 205 Ala Met Gly Leu Asp Ser Ile Leu Ile Ala Ile Ser Tyr Gly Phe Ile 210 215 220 Leu His Ala Val Phe His Leu Pro Ser His Asp Ala Gln His Lys Ala 225 230 235 240 Leu Ser Thr Cys Gly Ser His Ile Gly Ile Ile Leu Val Phe Tyr Ile 245 250 255 Pro Ala Phe Phe Ser Phe Leu Thr His Arg Phe Gly His 260 265 63 318 PRT Mus musculus VARIANT (286) Where Xaa is Thr, Leu, Gln or Arg 63 Met Ser Pro Gly Asn Ser Ser Trp Ile His Pro Ser Ser Phe Leu Leu 1 5 10 15 Leu Gly Ile Pro Gly Leu Glu Glu Leu Gln Phe Trp Leu Gly Leu Pro 20 25 30 Phe Gly Thr Val Tyr Leu Ile Ala Val Leu Gly Asn Val Ile Ile Leu 35 40 45 Phe Val Ile Tyr Leu Glu His Ser Leu His Gln Pro Met Phe Tyr Leu 50 55 60 Leu Ala Ile Leu Ala Val Thr Asp Leu Gly Leu Ser Thr Ala Thr Val 65 70 75 80 Pro Arg Ala Leu Gly Ile Phe Trp Phe Gly Phe His Lys Ile Ala Phe 85 90 95 Arg Asp Cys Val Ala Gln Met Phe Phe Ile His Leu Phe Thr Gly Ile 100 105 110 Glu Thr Phe Met Leu Val Ala Met Ala Phe Asp Arg Tyr Ile Ala Ile 115 120 125 Cys Asn Pro Leu Arg Tyr Asn Thr Ile Leu Thr Asn Arg Thr Ile Cys 130 135 140 Ile Ile Val Gly Val Gly Leu Phe Lys Asn Phe Ile Leu Val Phe Pro 145 150 155 160 Leu Ile Phe Leu Ile Leu Arg Leu Ser Phe Cys Gly His Asn Ile Ile 165 170 175 Pro His Thr Tyr Cys Glu His Met Gly Ile Ala Arg Leu Ala Cys Val 180 185 190 Ser Ile Lys Val Asn Val Leu Phe Gly Leu Ile Leu Ile Ser Met Ile 195 200 205 Leu Leu Asp Val Val Leu Ser Ala Leu Ser Tyr Ala Lys Ile Leu His 210 215 220 Ala Val Phe Lys Leu Pro Ser Trp Glu Ala Arg Leu Lys Ala Leu Asn 225 230 235 240 Thr Cys Gly Ser His Val Cys Val Ile Leu Ala Phe Phe Thr Pro Ala 245 250 255 Phe Phe Ser Phe Leu Thr His Arg Phe Gly His Asn Ile Pro Arg Tyr 260 265 270 Ile His Ile Leu Leu Ala Asn Leu Tyr Val Ile Ile Pro Xaa Ala Leu 275 280 285 Asn Pro Ile Ile Tyr Gly Val Arg Thr Lys Gln Ile Gln Asp Arg Ala 290 295 300 Val Thr Ile Leu Cys Asn Glu Val Gly Gln Leu Ala Asp Asp 305 310 315 64 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 64 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 65 315 PRT Homo sapiens 65 Met Glu Ile Val Ser Thr Gly Asn Glu Thr Ile Thr Glu Phe Val Leu 1 5 10 15 Leu Gly Phe Tyr Asp Ile Pro Glu Leu His Phe Leu Phe Phe Ile Val 20 25 30 Phe Thr Ala Val Tyr Val Phe Ile Ile Ile Gly Asn Met Leu Ile Ile 35 40 45 Val Ala Val Val Ser Ser Gln Arg Leu His Lys Pro Met Tyr Ile Phe 50 55 60 Leu Ala Asn Leu Ser Phe Leu Asp Ile Leu Tyr Thr Ser Ala Val Met 65 70 75 80 Pro Lys Met Leu Glu Gly Phe Leu Gln Glu Ala Thr Ile Ser Val Ala 85 90 95 Gly Cys Leu Leu Gln Phe Phe Ile Phe Gly Ser Leu Ala Thr Ala Glu 100 105 110 Cys Leu Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr Leu Ala Ile Cys 115 120 125 Tyr Pro Leu His Tyr Pro Leu Leu Met Gly Pro Arg Arg Tyr Met Gly 130 135 140 Leu Val Val Thr Thr Trp Leu Ser Gly Phe Val Val Asp Gly Leu Val 145 150 155 160 Val Ala Leu Val Ala Gln Leu Arg Phe Cys Gly Pro Asn His Ile Asp 165 170 175 Gln Phe Tyr Cys Asp Phe Met Leu Phe Val Gly Leu Ala Cys Ser Asp 180 185 190 Pro Arg Val Ala Gln Val Thr Thr Leu Ile Leu Ser Val Phe Cys Leu 195 200 205 Thr Ile Pro Phe Gly Leu Ile Leu Thr Ser Tyr Ala Arg Ile Val Val 210 215 220 Ala Val Leu Arg Val Pro Ala Gly Ala Ser Arg Arg Arg Ala Phe Ser 225 230 235 240 Thr Cys Ser Ser His Leu Ala Val Val Thr Thr Phe Tyr Gly Thr Leu 245 250 255 Met Ile Phe Tyr Val Ala Pro Ser Ala Val His Ser Gln Leu Leu Ser 260 265 270 Lys Val Phe Ser Leu Leu Tyr Thr Val Val Thr Pro Leu Phe Asn Pro 275 280 285 Val Ile Tyr Thr Met Arg Asn Lys Glu Val His Gln Ala Leu Arg Lys 290 295 300 Ile Leu Cys Ile Lys Gln Thr Glu Thr Leu Asp 305 310 315 66 315 PRT Homo sapiens 66 Met Glu Ile Val Ser Thr Gly Asn Glu Thr Ile Thr Glu Phe Val Leu 1 5 10 15 Leu Gly Phe Tyr Asp Ile Pro Glu Leu His Phe Leu Phe Phe Ile Val 20 25 30 Phe Thr Ala Val Tyr Val Phe Ile Ile Ile Gly Asn Met Leu Ile Ile 35 40 45 Val Ala Val Val Ser Ser Gln Arg Leu His Lys Pro Met Tyr Ile Phe 50 55 60 Leu Ala Asn Leu Ser Phe Leu Asp Ile Leu Tyr Thr Ser Ala Val Met 65 70 75 80 Pro Lys Met Leu Glu Gly Phe Leu Gln Glu Ala Thr Ile Ser Val Ala 85 90 95 Gly Cys Leu Leu Gln Phe Phe Ile Phe Gly Ser Leu Ala Thr Ala Glu 100 105 110 Cys Leu Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr Leu Ala Ile Cys 115 120 125 Tyr Pro Leu His Tyr Pro Leu Leu Met Gly Pro Arg Arg Tyr Met Gly 130 135 140 Leu Val Val Thr Thr Trp Leu Ser Gly Phe Val Val Asp Gly Leu Val 145 150 155 160 Val Ala Leu Val Thr Gln Leu Arg Phe Cys Gly Pro Asn His Ile Asp 165 170 175 Gln Phe Tyr Cys Asp Phe Met Leu Phe Val Gly Leu Ala Cys Ser Asp 180 185 190 Pro Arg Val Ala Gln Val Thr Thr Leu Ile Leu Ser Val Phe Cys Leu 195 200 205 Thr Ile Pro Phe Gly Leu Ile Leu Thr Ser Tyr Ala Arg Ile Val Val 210 215 220 Ala Val Leu Arg Val Pro Ala Gly Ala Ser Arg Arg Arg Ala Phe Ser 225 230 235 240 Thr Cys Ser Ser His Leu Ala Val Val Thr Thr Phe Tyr Gly Thr Leu 245 250 255 Met Ile Phe Tyr Val Ala Pro Ser Ala Val His Ser Gln Leu Leu Ser 260 265 270 Lys Val Phe Ser Leu Leu Tyr Thr Val Val Thr Pro Leu Phe Asn Pro 275 280 285 Val Ile Tyr Thr Met Arg Asn Lys Glu Val His Gln Ala Leu Arg Lys 290 295 300 Ile Leu Cys Ile Lys Gln Thr Glu Thr Leu Asp 305 310 315 67 292 PRT Marmota marmota 67 Pro Met Tyr Leu Phe Leu Gly Asn Leu Ser Phe Leu Glu Ile Leu Tyr 1 5 10 15 Thr Ser Thr Val Val Pro Lys Met Leu Glu Gly Phe Leu Gln Val Ala 20 25 30 Ala Ile Ser Val Thr Gly Cys Leu Thr Gln Phe Phe Ile Phe Gly Ser 35 40 45 Leu Ala Thr Ala Glu Cys Phe Leu Leu Ala Val Met Ala Tyr Asp Arg 50 55 60 Phe Leu Ala Ile Cys Tyr Pro Leu Arg Tyr Pro Leu Leu Met Gly Pro 65 70 75 80 Arg Trp Cys Met Gly Leu Val Val Thr Ala Trp Leu Ser Gly Phe Met 85 90 95 Val Asp Glu Leu Val Val Val Leu Met Ala Gln Leu Arg Phe Cys Gly 100 105 110 Ser Asn Arg Ile Asp His Phe Tyr Cys Asp Phe Met Pro Leu Val Val 115 120 125 Leu Ala Cys Ser Asp Pro Arg Val Ala Gln Val Thr Thr Phe Val Leu 130 135 140 Ser Val Val Phe Leu Thr Val Pro Phe Gly Leu Ile Leu Thr Ser Tyr 145 150 155 160 Ala Arg Ile Val Val Thr Val Leu Arg Val Pro Ala Gly Ala Ser Arg 165 170 175 Arg Lys Ala Phe Ser Thr Cys Ser Ser His Leu Ala Val Val Ser Thr 180 185 190 Phe Tyr Gly Thr Leu Met Val Leu Tyr Ile Val Pro Ser Ala Val His 195 200 205 Ser Gln Leu Leu Ser Lys Val Phe Ala Leu Leu Tyr Thr Val Val Thr 210 215 220 Pro Ile Phe Asn Pro Ile Ile Tyr Ser Phe Arg Asn Gln Glu Val Lys 225 230 235 240 Lys Ala Leu Arg Arg Thr Leu His Leu Ala Gln Gly Gln Asp Ala Asn 245 250 255 Thr Lys Lys Ser Ser Arg Asp Gly Gln Asp Val Lys Arg Ala Leu Arg 260 265 270 Arg Thr Leu His Leu Ala Gln Asp Gln Glu Ala Asn Thr Asn Lys Gly 275 280 285 Ser Lys Ile Gly 290 68 327 PRT Mus musculus 68 Met Glu Arg Arg Asn His Thr Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Ala Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Ala Tyr Val Leu Val Leu Thr Glu Asn Ile Leu Ile Ile Thr 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Glu Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Ile Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Leu Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Glu Val Lys Lys 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Gly Gln Asp Ala Asn Thr 305 310 315 320 Lys Lys Ser Ser Arg Asp Gly 325 69 327 PRT Rattus norvegicus VARIANT (35) Where Xaa is Asp, Val, Ser or Gly 69 Met Glu Arg Arg Asn His Ser Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Val Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Xaa Tyr Val Leu Val Leu Thr Glu Asn Met Leu Ile Ile Ile 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Lys Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Val Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Phe Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Asp Val Lys Arg 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Asp Gln Glu Ala Asn Thr 305 310 315 320 Asn Lys Gly Ser Lys Ile Gly 325 70 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 70 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 71 321 PRT Homo sapiens 71 Met Val Asn Leu Thr Ser Met Ser Gly Phe Leu Leu Met Gly Phe Ser 1 5 10 15 Asp Glu Arg Lys Leu Gln Ile Leu His Ala Leu Val Phe Leu Val Thr 20 25 30 Tyr Leu Leu Ala Leu Thr Gly Asn Leu Leu Ile Ile Thr Ile Ile Thr 35 40 45 Val Asp Arg Arg Leu His Ser Pro Met Tyr Tyr Phe Leu Lys His Leu 50 55 60 Ser Leu Leu Asp Leu Cys Phe Ile Ser Val Thr Val Pro Gln Ser Ile 65 70 75 80 Ala Asn Ser Leu Met Gly Asn Gly Tyr Ile Ser Leu Val Gln Cys Ile 85 90 95 Leu Gln Val Phe Phe Phe Ile Ala Leu Ala Ser Ser Glu Val Ala Ile 100 105 110 Leu Thr Val Met Ser Tyr Asp Arg Tyr Ala Ala Ile Cys Gln Pro Leu 115 120 125 His Tyr Glu Thr Ile Met Asp Pro Arg Ala Cys Arg His Ala Val Ile 130 135 140 Ala Val Trp Ile Ala Gly Gly Leu Ser Gly Leu Met His Ala Ala Ile 145 150 155 160 Asn Phe Ser Ile Pro Leu Cys Gly Lys Arg Val Ile His Gln Phe Phe 165 170 175 Cys Asp Val Pro Gln Met Leu Lys Leu Ala Cys Ser Tyr Glu Phe Ile 180 185 190 Asn Glu Ile Ala Leu Ala Ala Phe Thr Thr Ser Ala Ala Phe Ile Cys 195 200 205 Leu Ile Ser Ile Val Leu Ser Tyr Ile Arg Ile Phe Ser Thr Val Leu 210 215 220 Arg Ile Pro Ser Ala Glu Gly Arg Thr Lys Val Phe Ser Thr Cys Leu 225 230 235 240 Pro His Leu Phe Val Ala Thr Phe Phe Leu Ser Ala Ala Gly Phe Glu 245 250 255 Phe Leu Arg Leu Pro Ser Asp Ser Ser Ser Thr Val Asp Leu Val Phe 260 265 270 Ser Val Phe Tyr Thr Val Ile Pro Pro Thr Leu Asn Pro Val Ile Tyr 275 280 285 Ser Leu Arg Asn Asp Ser Met Lys Ala Ala Leu Arg Lys Met Leu Ser 290 295 300 Lys Glu Glu Leu Pro Gln Arg Lys Met Cys Leu Lys Ala Met Phe Lys 305 310 315 320 Leu 72 321 PRT Mus musculus 72 Met Thr Val Lys Asn Ile Thr Thr Met Ser Gly Phe Leu Leu Met Gly 1 5 10 15 Phe Ser Asp Asn Arg Glu Leu Gln Ile Leu Tyr Ala Leu Leu Phe Leu 20 25 30 Leu Thr Tyr Leu Leu Gly Ser Ala Gly Asn Phe Ile Ile Ile Thr Ile 35 40 45 Thr Thr Leu Asp Pro Gln Leu Gln Ser Pro Met Tyr Tyr Phe Leu Lys 50 55 60 His Leu Ser Ile Leu Asp Leu Ser Ser Leu Ser Val Thr Val Pro Gln 65 70 75 80 Tyr Val Asp Ser Ser Leu Ala Gly Ser Gly Tyr Ile Ser Tyr Gly Gln 85 90 95 Cys Met Leu Gln Ile Phe Phe Phe Ala Ala Phe Ala Trp Gly Glu Val 100 105 110 Ala Ile Leu Thr Val Met Ser Tyr Asp Arg Tyr Val Ala Ile Cys Leu 115 120 125 Pro Leu His Tyr Glu Val Ile Met Ser Pro Arg Lys Cys Thr Trp Ala 130 135 140 Val Thr Ser Val Trp Leu Ser Ser Val Ile Pro Gly Thr Leu Tyr Ile 145 150 155 160 Ala Ser Ile Phe Ser Ile Arg Phe Cys Arg Ala Lys Ile Ile His Gln 165 170 175 Leu Phe Cys Asp Val Pro Gln Leu Leu Lys Leu Ser Cys Ser Asn Asp 180 185 190 His Leu Val Val Ile Gly Met Val Ser Phe Met Thr Ala Val Ala Phe 195 200 205 Ala Cys Phe Val Gly Ile Val Ile Ser Tyr Val His Ile Phe Ser Thr 210 215 220 Val Leu Arg Met Pro Ser Ala Glu Ser Arg Ser Lys Val Phe Ser Thr 225 230 235 240 Cys Leu Pro His Leu Phe Val Val Ser Leu Phe Leu Ser Thr Gly Ser 245 250 255 Cys Ala Tyr Leu Asn Thr Ser Ser Asp Ser Pro Thr Ala Leu Glu Phe 260 265 270 Leu Phe Ser Ile Phe Tyr Thr Val Leu Pro Pro Thr Leu Asn Pro Val 275 280 285 Ile Tyr Ser Leu Arg Asn Glu Thr Ile Lys Ser Val Val Arg Lys Leu 290 295 300 Leu Leu Ser Ser Lys Phe Thr Val Arg Ile Ile Cys Pro Val Ala Thr 305 310 315 320 Asp 73 304 PRT Mus musculus 73 Met Arg Gly Phe Leu Leu Met Gly Phe Ser Asp Asn Arg Glu Leu Gln 1 5 10 15 Ile Leu His Ala Leu Phe Phe Leu Val Ala Tyr Leu Leu Gly Ser Ala 20 25 30 Gly Asn Val Ile Ile Ile Thr Ile Thr Thr Leu Asp Pro Gln Leu Gln 35 40 45 Ser Pro Met Tyr Tyr Phe Leu Lys His Leu Ser Ile Leu Asp Leu Ser 50 55 60 Ser Leu Ser Val Thr Val Pro Gln Tyr Val Asp Ile Cys Leu Thr Gln 65 70 75 80 Ser Gly Tyr Ile Ser Tyr Ala Gln Cys Met Leu Gln Ile Phe Phe Phe 85 90 95 Thr Gly Phe Ala Trp Gly Glu Val Ala Ile Leu Thr Val Met Ser Tyr 100 105 110 Asp Arg Tyr Val Ala Val Cys Leu Pro Leu His Tyr Glu Val Ile Met 115 120 125 Gly Pro Ser Lys Cys Arg Trp Ala Val Thr Ala Val Trp Leu Ser Ser 130 135 140 Val Ile Pro Gly Thr Leu Tyr Ile Ala Ser Ile Phe Ser Ile Arg Phe 145 150 155 160 Cys Gly Asp Arg Ile Ile His Gln Phe Phe Cys Asp Val Pro Gln Val 165 170 175 Leu Lys Leu Ser Cys Ser Asp Asp Tyr Leu Val Thr Val Gly Val Ala 180 185 190 Asp Phe Leu Ser Ala Val Ala Phe Ala Cys Phe Ile Gly Ile Val Asn 195 200 205 Ser Tyr Val His Ile Phe Ser Thr Val Leu Arg Met Pro Ser Ala Glu 210 215 220 Ser Arg Ser Lys Val Phe Ser Thr Cys Leu Pro His Leu Phe Val Val 225 230 235 240 Leu Leu Phe Leu Ser Thr Gly Ile Phe Ala Tyr Leu Asn Pro Thr Ser 245 250 255 Asp Ser Pro Thr Ala Leu Gln Phe Leu Val Ser Ile Phe Tyr Thr Val 260 265 270 Leu Pro Pro Thr Leu Asn Pro Val Ile Tyr Ser Leu Arg Asn Glu Thr 275 280 285 Ile Lys Ser Val Ile Arg Lys Leu Leu Leu Ser Ser Lys Phe Thr Gly 290 295 300 74 320 PRT Mus musculus 74 Met Ile Val Glu Asn Ile Thr Thr Met Ser Gly Phe Leu Leu Met Gly 1 5 10 15 Phe Ser Asp Asn His Glu Leu Gln Ile Leu Gln Ala Leu Leu Phe Leu 20 25 30 Val Thr Tyr Leu Val Gly Ser Ala Gly Asn Val Ile Ile Ile Thr Ile 35 40 45 Thr Thr Leu Asp Pro Gln Leu Gln Ser Pro Met Tyr Tyr Phe Leu Lys 50 55 60 His Leu Ser Ile Leu Asp Leu Ser Ser Leu Ser Val Thr Val Pro Gln 65 70 75 80 Tyr Val Asp Ser Ser Leu Ala Gln Ser Gly Tyr Ile Ser Tyr Ala Gln 85 90 95 Cys Met Leu Gln Ile Phe Phe Phe Thr Ala Phe Ala Trp Gly Glu Leu 100 105 110 Ala Ile Leu Thr Val Met Ser Tyr Asp Arg Tyr Val Ala Ile Cys Leu 115 120 125 Pro Leu His Tyr Glu Val Ile Met Ser Pro Arg Lys Cys Thr Trp Ala 130 135 140 Val Ala Thr Val Trp Leu Ser Gly Gly Ile Ser Gly Thr Leu Tyr Ile 145 150 155 160 Thr Gly Thr Leu Phe Ile Arg Phe Cys Gly Asp Lys Ile Ile His Gln 165 170 175 Phe Phe Cys Asp Val Pro Gln Leu Leu Lys Leu Ser Cys Ser Asn Asp 180 185 190 His Leu Val Ile Met Asp Met Val Ser Phe Leu Thr Ala Val Ser Phe 195 200 205 Ala Cys Phe Thr Gly Ile Val Ile Ser Tyr Val His Ile Phe Ser Thr 210 215 220 Val Leu Arg Met Pro Ser Ala Glu Ser Arg Ser Lys Val Phe Ser Thr 225 230 235 240 Cys Leu Pro His Leu Phe Val Val Ser Leu Phe Leu Ser Thr Gly Ala 245 250 255 Phe Ala Tyr Leu Asn Leu Thr Ser Asp Ser Ser Thr Ala Leu Glu Phe 260 265 270 Leu Leu Ser Ile Phe Tyr Thr Val Leu Pro Pro Thr Leu Asn Pro Val 275 280 285 Ile Tyr Ser Leu Arg Asn Glu Thr Ile Lys Asn Val Val Arg Lys Leu 290 295 300 Leu Leu Ser Thr Lys Phe Thr Val Arg Ile Ile Phe Ser Cys Cys Phe 305 310 315 320 75 312 PRT Mus musculus 75 Met Ile Met Glu Asn Ile Thr Thr Met Ser Gly Phe Leu Leu Met Gly 1 5 10 15 Phe Ser Asp Asn Arg Glu Leu Gln Ile Leu Gln Ala Leu Leu Phe Leu 20 25 30 Val Thr Tyr Leu Val Gly Ser Ala Gly Asn Phe Ile Ile Ile Thr Ile 35 40 45 Thr Thr Leu Asp Pro Gln Leu Lys Ser Pro Met Tyr Tyr Phe Leu Lys 50 55 60 His Leu Ser Ile Leu Asp Leu Ser Ser Leu Ser Val Thr Val Pro Gln 65 70 75 80 Tyr Val Asp Ser Ser Leu Ala Arg Ser Gly Tyr Ile Ser Tyr Glu Gln 85 90 95 Cys Met Leu Gln Ile Phe Phe Phe Thr Cys Phe Ala Trp Asp Glu Met 100 105 110 Ala Ile Leu Thr Val Met Ser Tyr Asp Arg Tyr Val Ala Val Cys Leu 115 120 125 Pro Leu His Tyr Glu Val Ile Met Ser Pro Arg Lys Cys Thr Trp Ala 130 135 140 Leu Ala Ala Val Trp Leu Ser Gly Gly Val Ser Gly Thr Leu Tyr Thr 145 150 155 160 Ala Ser Thr Leu Ser Ile Arg Phe Cys Gly Asp Arg Ile Ile His Gln 165 170 175 Phe Phe Cys Asp Val Pro Gln Val Leu Lys Leu Ser Cys Ser Asn Asp 180 185 190 Tyr Leu Leu Thr Ile Gly Val Ala Asn Ile Leu Ser Ala Val Ala Phe 195 200 205 Ala Cys Phe Ile Gly Ile Val Ile Ser Tyr Val His Ile Phe Ser Thr 210 215 220 Val Leu Arg Met Pro Ser Ala Glu Ser Arg Tyr Lys Val Phe Ser Thr 225 230 235 240 Cys Leu Pro His Leu Phe Val Val Ser Leu Phe Leu Ser Thr Ser Thr 245 250 255 Phe Ala Tyr Leu Asn Pro Thr Ala Asp Ser Pro Thr Ala Leu Glu Phe 260 265 270 Leu Phe Ser Ile Leu Tyr Thr Val Leu Pro Pro Thr Ile Asn Pro Val 275 280 285 Ile Tyr Ser Leu Arg Asn Glu Thr Ile Lys Ser Val Val Arg Lys Leu 290 295 300 Leu Ser Ser Thr Lys Phe Thr Val 305 310 76 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 76 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 77 310 PRT Homo sapiens 77 Met Gly Asp Asn Ile Thr Ser Ile Thr Glu Phe Leu Leu Leu Gly Phe 1 5 10 15 Pro Val Gly Pro Arg Ile Gln Met Leu Leu Phe Gly Leu Phe Ser Leu 20 25 30 Phe Tyr Val Phe Thr Leu Leu Gly Asn Gly Thr Ile Leu Gly Leu Ile 35 40 45 Ser Leu Asp Ser Arg Leu His Ala Pro Met Tyr Phe Phe Leu Ser His 50 55 60 Leu Ala Val Val Asp Ile Ala Tyr Ala Cys Asn Thr Val Pro Arg Met 65 70 75 80 Leu Val Asn Leu Leu His Pro Ala Lys Pro Ile Ser Phe Ala Gly Arg 85 90 95 Met Met Gln Thr Phe Leu Phe Ser Thr Phe Ala Val Thr Glu Cys Leu 100 105 110 Leu Leu Val Val Met Ser Tyr Asp Leu Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg Tyr Leu Ala Ile Met Thr Trp Arg Val Cys Ile Thr Leu Ala 130 135 140 Val Thr Ser Trp Thr Thr Gly Val Leu Leu Ser Leu Ile His Leu Val 145 150 155 160 Leu Leu Leu Pro Leu Pro Phe Cys Arg Pro Gln Lys Ile Tyr His Phe 165 170 175 Phe Cys Glu Ile Leu Ala Val Leu Lys Leu Ala Cys Ala Asp Thr His 180 185 190 Ile Asn Glu Asn Met Val Leu Ala Gly Ala Ile Ser Gly Leu Val Gly 195 200 205 Pro Leu Ser Thr Ile Val Val Ser Tyr Met Cys Ile Leu Cys Ala Ile 210 215 220 Leu Gln Ile Gln Ser Arg Glu Val Gln Arg Lys Ala Phe Cys Thr Cys 225 230 235 240 Phe Ser His Leu Cys Val Ile Gly Leu Phe Tyr Gly Thr Ala Ile Ile 245 250 255 Met Tyr Val Gly Pro Arg Tyr Gly Asn Pro Lys Glu Gln Lys Lys Tyr 260 265 270 Leu Leu Leu Phe His Ser Leu Phe Asn Pro Met Leu Asn Pro Leu Ile 275 280 285 Cys Ser Leu Arg Asn Ser Glu Val Lys Asn Thr Leu Lys Arg Val Leu 290 295 300 Gly Val Glu Arg Ala Leu 305 310 78 310 PRT Homo sapiens 78 Met Gly Asp Asn Ile Thr Ser Ile Arg Glu Phe Leu Leu Leu Gly Phe 1 5 10 15 Pro Val Gly Pro Arg Ile Gln Met Leu Leu Phe Gly Leu Phe Ser Leu 20 25 30 Phe Tyr Val Phe Thr Leu Leu Gly Asn Gly Thr Ile Leu Gly Leu Ile 35 40 45 Ser Leu Asp Ser Arg Leu His Ala Pro Met Tyr Phe Phe Leu Ser His 50 55 60 Leu Ala Val Val Asp Ile Ala Tyr Ala Cys Asn Thr Val Pro Arg Met 65 70 75 80 Leu Val Asn Leu Leu His Pro Ala Lys Pro Ile Ser Phe Ala Gly Arg 85 90 95 Met Met Gln Thr Phe Leu Phe Ser Thr Phe Ala Val Thr Glu Cys Leu 100 105 110 Leu Leu Val Val Met Ser Tyr Asp Leu Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg Tyr Leu Ala Ile Met Thr Trp Arg Val Cys Ile Thr Leu Ala 130 135 140 Val Thr Ser Trp Thr Thr Gly Val Leu Leu Ser Leu Ile His Leu Val 145 150 155 160 Leu Leu Leu Pro Leu Pro Phe Cys Arg Pro Gln Lys Ile Tyr His Phe 165 170 175 Phe Cys Glu Ile Leu Ala Val Leu Lys Leu Ala Cys Ala Asp Thr His 180 185 190 Ile Asn Glu Asn Met Val Leu Ala Gly Ala Ile Ser Gly Leu Val Gly 195 200 205 Pro Leu Ser Thr Ile Val Val Ser Tyr Met Cys Ile Leu Cys Ala Ile 210 215 220 Leu Gln Ile Gln Ser Arg Glu Val Gln Arg Lys Ala Phe Arg Thr Cys 225 230 235 240 Phe Ser His Leu Cys Val Ile Gly Leu Val Tyr Gly Thr Ala Ile Ile 245 250 255 Met Tyr Val Gly Pro Arg Tyr Gly Asn Pro Lys Glu Gln Lys Lys Tyr 260 265 270 Leu Leu Leu Phe His Ser Leu Phe Asn Pro Met Leu Asn Pro Leu Ile 275 280 285 Cys Ser Leu Arg Asn Ser Glu Val Lys Asn Thr Leu Lys Arg Val Leu 290 295 300 Gly Val Glu Arg Ala Leu 305 310 79 217 PRT Homo sapiens 79 Ile Ile Asp Ile Ser Tyr Ala Ser Asn Lys Val Pro Lys Met Leu Thr 1 5 10 15 Asn Leu Gly Leu Asn Lys Arg Lys Thr Ile Ser Phe Val Pro Cys Thr 20 25 30 Met Gln Thr Phe Leu Tyr Met Ala Phe Ala His Thr Glu Cys Leu Ile 35 40 45 Leu Val Met Met Ser Tyr Asp Arg Tyr Met Ala Ile Cys His Pro Leu 50 55 60 Gln Tyr Ser Val Ile Met Arg Trp Gly Val Cys Thr Val Leu Ala Val 65 70 75 80 Thr Ser Trp Ala Cys Gly Ser Leu Leu Ala Leu Val His Val Val Leu 85 90 95 Ile Leu Arg Leu Pro Phe Cys Gly Pro His Glu Ile Asn His Phe Phe 100 105 110 Cys Glu Ile Leu Ser Val Leu Lys Leu Ala Cys Ala Asp Thr Trp Leu 115 120 125 Asn Gln Val Val Ile Phe Ala Ala Ser Val Phe Ile Leu Val Gly Pro 130 135 140 Leu Cys Leu Val Leu Val Ser Tyr Ser Arg Ile Leu Ala Ala Ile Leu 145 150 155 160 Arg Ile Gln Ser Gly Glu Gly Arg Arg Lys Ala Phe Ser Thr Cys Ser 165 170 175 Ser His Leu Cys Met Val Gly Leu Phe Phe Gly Ser Ala Ile Val Met 180 185 190 Tyr Met Ala Pro Lys Ser Arg His Pro Glu Glu Gln Gln Lys Val Leu 195 200 205 Ser Leu Phe Tyr Ser Leu Phe Asn Pro 210 215 80 217 PRT Homo sapiens 80 Ile Ile Asp Ile Ser Tyr Ala Ser Asn Asn Val Pro Lys Met Leu Thr 1 5 10 15 Asn Leu Gly Leu Asn Lys Arg Lys Thr Ile Ser Phe Val Pro Cys Thr 20 25 30 Met Gln Thr Phe Leu Tyr Met Ala Phe Ala His Thr Glu Cys Leu Ile 35 40 45 Leu Val Met Met Ser Tyr Asp Arg Tyr Met Ala Ile Cys His Pro Leu 50 55 60 Gln Tyr Ser Val Ile Met Arg Trp Gly Val Cys Thr Val Leu Ala Val 65 70 75 80 Thr Ser Trp Ala Cys Gly Ser Leu Leu Ala Leu Val His Val Val Leu 85 90 95 Ile Leu Arg Leu Pro Phe Cys Gly Pro His Glu Ile Asn His Phe Phe 100 105 110 Cys Glu Ile Leu Ser Val Leu Lys Leu Ala Cys Ala Asp Thr Trp Leu 115 120 125 Asn Gln Val Val Ile Phe Ala Ala Ser Val Phe Ile Leu Val Gly Pro 130 135 140 Leu Cys Leu Val Leu Val Ser Tyr Ser Arg Ile Leu Ala Ala Ile Leu 145 150 155 160 Gly Ile Gln Ser Gly Glu Gly Arg Arg Lys Ala Phe Ser Thr Cys Ser 165 170 175 Ser His Leu Cys Met Val Gly Leu Phe Phe Gly Ser Ala Ile Val Met 180 185 190 Tyr Met Ala Pro Lys Ser Arg His Pro Glu Glu Gln Gln Lys Val Leu 195 200 205 Ser Leu Phe Tyr Ser Leu Phe Asn Pro 210 215 81 217 PRT Homo sapiens 81 Ile Ile Asp Ile Ser Tyr Ala Ser Asn Lys Val Pro Lys Met Leu Thr 1 5 10 15 Asn Leu Gly Leu Asn Lys Arg Lys Thr Ile Ser Phe Val Pro Cys Thr 20 25 30 Met Gln Thr Phe Leu Tyr Met Ala Phe Ala His Thr Glu Cys Leu Ile 35 40 45 Leu Val Met Met Ser Tyr Asp Arg Tyr Met Ala Ile Cys His Pro Leu 50 55 60 Gln Tyr Ser Val Ile Met Arg Trp Gly Val Cys Thr Val Leu Ala Val 65 70 75 80 Thr Ser Trp Ala Cys Gly Ser Leu Leu Ala Leu Val His Val Val Leu 85 90 95 Ile Leu Arg Leu Pro Phe Cys Gly Pro His Glu Ile Asn His Phe Phe 100 105 110 Cys Glu Ile Leu Ser Val Leu Lys Leu Ala Cys Ala Asp Thr Trp Leu 115 120 125 Asn Gln Val Val Ile Phe Ala Ala Ser Val Phe Ile Leu Val Gly Pro 130 135 140 Leu Cys Leu Val Leu Val Ser Tyr Ser Arg Ile Leu Ala Ala Ile Leu 145 150 155 160 Gly Ile Gln Ser Gly Glu Gly Arg Arg Lys Ala Phe Ser Thr Cys Ser 165 170 175 Ser His Leu Cys Met Val Gly Leu Phe Phe Gly Ser Ala Ile Val Met 180 185 190 Tyr Met Ala Pro Lys Ser Arg His Pro Glu Glu Gln Gln Lys Val Leu 195 200 205 Ser Leu Phe Tyr Ser Leu Phe Asn Pro 210 215 82 194 PRT Artificial Sequence Description of Artificial Sequence 7tm_1, 7 transmembrane receptor domain sequence 82 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Leu Pro Thr Ala Leu 165 170 175 Leu Ile Thr Leu Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile 180 185 190 Ile Tyr 83 321 PRT Homo sapiens 83 Met Glu Arg Lys Asn Gln Thr Ala Ile Thr Glu Phe Ile Ile Leu Gly 1 5 10 15 Phe Ser Asn Leu Asn Glu Leu Gln Phe Leu Leu Phe Thr Ile Phe Phe 20 25 30 Leu Thr Tyr Phe Cys Thr Leu Gly Gly Asn Ile Leu Ile Ile Leu Thr 35 40 45 Thr Val Thr Asp Pro His Leu His Thr Pro Met Tyr Tyr Phe Leu Gly 50 55 60 Asn Leu Ala Phe Ile Asp Ile Cys Tyr Thr Thr Ser Asn Val Pro Gln 65 70 75 80 Met Met Val His Leu Leu Ser Lys Lys Lys Ser Ile Ser Tyr Val Gly 85 90 95 Cys Val Val Gln Leu Phe Ala Phe Val Phe Phe Val Gly Ser Glu Cys 100 105 110 Leu Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Ile Ala Ile Cys Asn 115 120 125 Pro Leu Arg Tyr Ser Val Ile Leu Ser Lys Val Leu Cys Asn Gln Leu 130 135 140 Ala Ala Ser Cys Trp Ala Ala Gly Phe Leu Asn Ser Val Val His Thr 145 150 155 160 Val Leu Thr Phe Cys Leu Pro Phe Cys Gly Asn Asn Gln Ile Asn Tyr 165 170 175 Phe Phe Cys Asp Ile Pro Pro Leu Leu Ile Leu Ser Cys Gly Asn Thr 180 185 190 Ser Val Asn Glu Leu Ala Leu Leu Ser Thr Gly Val Phe Ile Gly Trp 195 200 205 Thr Pro Phe Leu Cys Ile Val Leu Ser Tyr Ile Cys Ile Ile Ser Thr 210 215 220 Ile Leu Arg Ile Gln Ser Ser Glu Gly Arg Arg Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Ala Ile Val Phe Leu Phe Tyr Gly Ser Ala Ile 245 250 255 Phe Thr Tyr Val Arg Pro Ile Ser Thr Tyr Ser Leu Lys Lys Asp Arg 260 265 270 Leu Val Ser Val Leu Tyr Ser Val Val Thr Pro Met Leu Asn Pro Ile 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Asp Ile Lys Glu Ala Val Lys Thr Ile 290 295 300 Gly Ser Lys Trp Gln Pro Pro Ile Ser Ser Leu Asp Ser Lys Leu Thr 305 310 315 320 Tyr 84 327 PRT Mus musculus 84 Met Glu Arg Arg Asn His Thr Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Ala Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Ala Tyr Val Leu Val Leu Thr Glu Asn Ile Leu Ile Ile Thr 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Glu Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Ile Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Leu Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Glu Val Lys Lys 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Gly Gln Asp Ala Asn Thr 305 310 315 320 Lys Lys Ser Ser Arg Asp Gly 325 85 327 PRT Rattus norvegicus VARIANT (35) Where Xaa is Asp, Val, Ser or Gly 85 Met Glu Arg Arg Asn His Ser Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Val Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Xaa Tyr Val Leu Val Leu Thr Glu Asn Met Leu Ile Ile Ile 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Lys Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Val Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Phe Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Asp Val Lys Arg 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Asp Gln Glu Ala Asn Thr 305 310 315 320 Asn Lys Gly Ser Lys Ile Gly 325 86 314 PRT Mus musculus 86 Met Leu Asp Met Asn Ile Thr Leu Val Ser Glu Phe Ile Leu Val Gly 1 5 10 15 Phe Pro Thr Ala Pro Trp Leu Gln Ile Leu Leu Phe Phe Ile Phe Leu 20 25 30 Val Val Tyr Met Leu Ile Ile Ala Glu Asn Leu Val Ile Ile Phe Thr 35 40 45 Val Trp Ser Thr Gly Ser Leu His Lys Pro Met Tyr Tyr Phe Leu Ser 50 55 60 Ser Met Ser Phe Leu Glu Ile Trp Tyr Val Ser Val Thr Val Pro Lys 65 70 75 80 Met Leu Asp Gly Phe Leu Leu Gln Arg Arg His Ile Ser Phe Thr Gly 85 90 95 Cys Met Thr Gln Leu Tyr Phe Phe Ile Ser Leu Ala Cys Thr Glu Cys 100 105 110 Val Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Pro Val Ile Met Thr Thr Val Tyr Cys Met Gln Leu 130 135 140 Met Ala Leu Ser Tyr Phe Ser Gly Phe Met Val Ser Val Val Lys Val 145 150 155 160 Tyr Phe Ile Ser His Val Ala Phe Cys Gly Ser Asn Val Met Asn His 165 170 175 Phe Phe Cys Asp Ile Ser Pro Ile Leu Lys Leu Ala Cys Lys Asp Met 180 185 190 Ser Thr Ala Glu Leu Val Asp Phe Ala Leu Ala Ile Val Ile Leu Val 195 200 205 Phe Pro Leu Ile Thr Thr Val Leu Ser Tyr Val Tyr Ile Val Ser Thr 210 215 220 Ile Leu Arg Ile Pro Ser Thr Gln Gly Arg Lys Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Thr Val Val Ile Ile Tyr Tyr Thr Ala Met Ile 245 250 255 Phe Met Tyr Val Arg Pro Arg Ala Ile Ala Ser Phe Asn Ser Asn Lys 260 265 270 Leu Ile Ser Ala Val Tyr Ala Val Leu Thr Pro Met Leu Asn Pro Phe 275 280 285 Ile Tyr Cys Leu Arg Asn Arg Glu Val Lys Asp Ala Ile Lys Lys Thr 290 295 300 Leu Gly Gly Gly Gln Cys Phe Leu Leu Cys 305 310 87 317 PRT Mus musculus 87 Met Glu Gly Lys Asn Gln Thr Ala Pro Ser Glu Phe Ile Ile Leu Gly 1 5 10 15 Phe Asp His Leu Asn Glu Leu Gln Tyr Leu Leu Phe Thr Ile Phe Phe 20 25 30 Leu Thr Tyr Ile Cys Thr Leu Gly Gly Asn Val Phe Ile Ile Val Val 35 40 45 Thr Ile Ala Asp Ser His Leu His Thr Pro Met Tyr Tyr Phe Leu Gly 50 55 60 Asn Leu Ala Leu Ile Asp Ile Cys Tyr Thr Thr Thr Asn Val Pro Gln 65 70 75 80 Met Met Val His Leu Leu Ser Glu Lys Lys Ile Ile Ser Tyr Gly Gly 85 90 95 Cys Val Thr Gln Leu Phe Ala Phe Ile Phe Phe Val Gly Ser Glu Cys 100 105 110 Leu Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Ile Ala Ile Cys Lys 115 120 125 Pro Leu Arg Tyr Ser Phe Ile Met Asn Lys Ala Leu Cys Ser Trp Leu 130 135 140 Ala Ala Ser Cys Trp Thr Cys Gly Phe Leu Asn Ser Val Leu His Thr 145 150 155 160 Val Leu Thr Phe His Leu Pro Phe Cys Gly Asn Asn Gln Ile Asn Tyr 165 170 175 Phe Phe Cys Asp Ile Pro Pro Leu Leu Ile Leu Ser Cys Gly Asp Thr 180 185 190 Ser Leu Asn Glu Leu Ala Leu Leu Ser Ile Gly Ile Leu Ile Gly Trp 195 200 205 Thr Pro Phe Leu Cys Ile Ile Leu Ser Tyr Leu Tyr Ile Ile Ser Thr 210 215 220 Ile Leu Arg Ile Arg Ser Ser Glu Gly Arg Gln Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Leu Ile Val Ile Leu Tyr Tyr Gly Ser Ala Ile 245 250 255 Phe Thr Tyr Val Arg Pro Ile Ser Ser Tyr Ser Leu Glu Lys Asp Arg 260 265 270 Leu Ile Ser Val Leu Tyr Ser Val Phe Thr Pro Met Leu Asn Pro Ile 275 280 285 Ile Tyr Ala Leu Arg Asn Lys Asp Ile Lys Glu Ala Val Lys Ala Ile 290 295 300 Gly Arg Lys Trp Gln Pro Pro Val Phe Ser Ser Asp Met 305 310 315 88 253 PRT Artificial Sequence Description of Artificial Sequence 7tm_1, 7 transmembrane receptor domain sequence 88 Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg Thr 1 5 10 15 Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu Phe 20 25 30 Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly Asp 35 40 45 Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe Val 50 55 60 Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile Asp 65 70 75 80 Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg Thr 85 90 95 Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala Leu 100 105 110 Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val Glu 115 120 125 Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser Val 130 135 140 Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu Pro 145 150 155 160 Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu Arg 165 170 175 Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser Glu 180 185 190 Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val Leu 195 200 205 Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys Leu 210 215 220 Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu Trp 225 230 235 240 Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 89 213 PRT Homo sapiens 89 Phe Ile Asp Ala Cys Tyr Ser Ser Val Asn Thr Pro Lys Leu Ile Thr 1 5 10 15 Asp Ser Leu Tyr Glu Asn Lys Thr Ile Leu Phe Asn Gly Cys Met Thr 20 25 30 Gln Val Phe Gly Glu His Phe Phe Arg Gly Val Glu Val Ile Leu Leu 35 40 45 Thr Val Met Ala Tyr Asp His Tyr Val Ala Ile Cys Lys Pro Leu His 50 55 60 Tyr Thr Thr Ile Met Lys Gln His Val Cys Ser Leu Leu Val Gly Val 65 70 75 80 Ser Trp Val Gly Gly Phe Leu His Ala Thr Ile Gln Ile Leu Phe Ile 85 90 95 Cys Gln Leu Pro Phe Cys Gly Pro Asn Val Ile Asp His Phe Met Cys 100 105 110 Asp Leu Tyr Thr Leu Ile Asn Leu Ala Cys Thr Asn Thr His Thr Leu 115 120 125 Gly Leu Phe Ile Ala Ala Asn Ser Gly Phe Ile Cys Leu Leu Asn Cys 130 135 140 Leu Leu Leu Leu Val Ser Cys Val Val Ile Leu Tyr Ser Leu Lys Thr 145 150 155 160 His Ser Leu Glu Ala Arg His Glu Ala Leu Ser Thr Cys Val Ser His 165 170 175 Ile Thr Val Val Ile Leu Ser Phe Ile Pro Cys Ile Phe Val Tyr Met 180 185 190 Arg Pro Pro Ala Thr Leu Pro Ile Asp Lys Ala Val Ala Val Phe Tyr 195 200 205 Thr Met Ile Thr Ser 210 90 308 PRT Mus musculus 90 Met Glu Ile Pro His Asn Ile Thr Glu Phe Phe Met Leu Gly Leu Ser 1 5 10 15 Gln Arg Pro Glu Ile Gln Arg Leu Leu Phe Val Val Phe Leu Val Ile 20 25 30 Tyr Ala Val Thr Val Cys Gly Asn Met Leu Ile Val Val Thr Val Thr 35 40 45 Phe Ser Ser Ser Leu Ala Ser Pro Met Tyr Phe Phe Leu Ser Asn Leu 50 55 60 Ser Phe Ile Asp Thr Cys Tyr Ser Ser Ser Leu Ala Pro Lys Leu Ile 65 70 75 80 Ala Asp Ser Leu Tyr Glu Gly Thr Thr Leu Ser Tyr Glu Gly Cys Met 85 90 95 Ala Gln Leu Phe Gly Ala His Phe Leu Gly Gly Val Glu Ile Ile Leu 100 105 110 Leu Thr Val Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Lys Pro Leu 115 120 125 His Tyr Thr Thr Thr Met Thr Arg His Leu Cys Val Val Leu Val Ala 130 135 140 Val Ala Trp Leu Gly Gly Phe Leu His Ser Leu Val Gln Ile Leu Leu 145 150 155 160 Ile Phe Gln Leu Pro Phe Cys Gly Pro Asn Val Ile Asn His Phe Val 165 170 175 Cys Asp Leu Tyr Pro Leu Leu Glu Leu Ala Cys Thr Asn Thr Tyr Val 180 185 190 Ile Gly Leu Leu Val Val Ala Asn Ser Gly Val Ile Cys Leu Leu Asn 195 200 205 Phe Leu Met Leu Ala Ala Ser Tyr Ile Val Ile Leu His Ser Leu Arg 210 215 220 Ser His Ser Ala Glu Gly Arg Arg Lys Ala Leu Ser Thr Cys Gly Ala 225 230 235 240 His Phe Thr Val Val Thr Met Phe Phe Val Pro Cys Ile Phe Ser Tyr 245 250 255 Met Arg Pro Ser Thr Thr Leu Pro Ile Asp Lys Asn Met Ala Val Phe 260 265 270 Tyr Gly Ile Leu Thr Pro Met Leu Asn Pro Leu Ile Tyr Thr Leu Arg 275 280 285 Asn Glu Glu Val Lys Asp Ala Met Arg Lys Leu Phe Thr Arg Ser Glu 290 295 300 Val Val Gly Ala 305 91 302 PRT Mus musculus 91 Met Asp Ser Pro Arg Asn Val Thr Glu Phe Phe Met Leu Gly Leu Ser 1 5 10 15 Gln Asn Pro Gln Val Gln Arg Met Leu Phe Gly Leu Phe Leu Leu Val 20 25 30 Phe Leu Val Ser Val Gly Gly Asn Met Leu Ile Ile Ile Thr Ile Thr 35 40 45 Phe Ser Pro Thr Leu Gly Ser Pro Met Tyr Phe Phe Leu Ser Tyr Leu 50 55 60 Ser Phe Ile Asp Thr Cys Tyr Ser Ser Cys Met Thr Pro Lys Leu Ile 65 70 75 80 Ala Asp Ser Leu His Glu Gly Arg Ala Ile Ser Phe Glu Gly Cys Leu 85 90 95 Ala Gln Phe Phe Val Ala His Leu Leu Gly Gly Thr Glu Ile Ile Leu 100 105 110 Leu Thr Val Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Lys Pro Leu 115 120 125 His Tyr Thr Thr Thr Met Thr Arg His Val Cys Ile Val Leu Val Ala 130 135 140 Val Ala Trp Leu Gly Gly Ile Leu His Ser Thr Ala Gln Leu Phe Leu 145 150 155 160 Val Leu Gln Leu Pro Phe Cys Gly Pro Asn Val Ile Asn His Phe Val 165 170 175 Cys Asp Leu Tyr Pro Leu Leu Glu Leu Ala Cys Thr Asp Thr Tyr Val 180 185 190 Ile Gly Leu Leu Val Val Ala Asn Ser Gly Val Ile Cys Leu Leu Asn 195 200 205 Phe Leu Met Leu Ala Ala Ser Tyr Ile Val Ile Leu Arg Thr Leu Arg 210 215 220 Ser His Ser Ala Glu Gly Arg Arg Lys Ala Leu Ser Thr Cys Gly Ala 225 230 235 240 His Phe Thr Val Val Ala Leu Phe Phe Val Pro Cys Ile Phe Ile Tyr 245 250 255 Met Arg Pro Ser Ser Thr Leu Ser Ile Asp Lys Ile Val Ala Val Phe 260 265 270 Tyr Cys Ile Leu Thr Pro Met Phe Asn Pro Leu Ile Tyr Thr Leu Arg 275 280 285 Asn Ala Glu Val Lys Asn Ala Met Lys Asn Leu Trp Arg Lys 290 295 300 92 307 PRT Rattus norvegicus 92 Met Gly Glu Asn Asn Asn Ile Thr Glu Phe Ile Leu Leu Gly Leu Thr 1 5 10 15 Gln Asp Pro Asp Gly Arg Lys Ala Leu Phe Val Ile Phe Phe Leu Ile 20 25 30 Tyr Ile Val Thr Met Met Gly Asn Leu Leu Ile Val Val Thr Val Ile 35 40 45 Ala Ser Pro Ser Leu Gly Ser Pro Met Tyr Phe Phe Leu Ala Ser Leu 50 55 60 Ser Leu Leu Asp Ala Leu Phe Ser Thr Ala Ile Ser Pro Lys Leu Ile 65 70 75 80 Ala Asp Leu Leu Tyr Asp Gln Lys Thr Ile Ser Phe Arg Ala Cys Met 85 90 95 Ser Gln Leu Phe Ile Glu His Leu Phe Gly Gly Val Asp Ile Val Ile 100 105 110 Leu Val Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Lys Pro Leu 115 120 125 His Tyr Leu Ala Ile Met Asn Arg Arg Val Cys Ile Thr Leu Leu Ile 130 135 140 Phe Ala Trp Thr Gly Gly Phe Thr His Ser Leu Ile Gln Ile Val Phe 145 150 155 160 Val Tyr Asn Leu Pro Phe Cys Gly Pro Asn Val Ile Asp His Phe Ile 165 170 175 Cys Asp Met Ser Pro Leu Leu Val Leu Ala Cys Thr Asp Thr Tyr Phe 180 185 190 Ile Gly Leu Thr Val Ile Ala Asn Gly Gly Val Asn Cys Ile Val Ile 195 200 205 Phe Thr Leu Leu Leu Gly Ser Tyr Gly Ile Ile Leu Arg Ser Leu Lys 210 215 220 Thr Gln Ser Gln Glu Gly Arg Arg Lys Ala Leu Ser Thr Cys Ser Ser 225 230 235 240 His Ile Leu Val Val Ile Leu Phe Phe Val Pro Cys Ile Phe Met Tyr 245 250 255 Ala Arg Pro Val Tyr Asn Phe Pro Ile Asp Lys Cys Ile Thr Val Phe 260 265 270 Tyr Thr Ile Ile Thr Pro Met Leu Asn Pro Leu Ile Tyr Thr Leu Arg 275 280 285 Asn Ser Glu Ile Lys Ser Cys Met Lys Lys Leu Trp Cys Lys Met Leu 290 295 300 His Ala Asp 305 93 189 PRT Mus musculus 93 Ser Phe Leu Ser Leu Ile Asp Gly Cys Cys Ser Ser Ser Met Thr Pro 1 5 10 15 Lys Met Leu Ala Asp Ser Leu Ser Val Arg Lys Thr Ile Ser Phe Ser 20 25 30 Gly Cys Met Thr Gln Val Phe Ala Glu His Phe Phe Gly Ala Ala Glu 35 40 45 Ile Ile Leu Leu Thr Val Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys 50 55 60 Lys Pro Leu Arg Tyr Thr Ile Ile Met Asn Arg Phe Val Cys Gly Leu 65 70 75 80 Leu Val Gly Val Ala Trp Ala Gly Gly Phe Ile His Ala Thr Ile Gln 85 90 95 Ile Leu Phe Thr Val Trp Leu Pro Phe Cys Gly Pro Asn Val Ile Asp 100 105 110 His Phe Met Cys Asp Leu Thr Pro Leu Leu Lys Leu Val Cys Met Asp 115 120 125 Thr His Asn Leu Gly Leu Phe Val Ala Ala Asn Ser Gly Phe Ile Cys 130 135 140 Leu Leu Asn Phe Leu Leu Leu Met Ile Ser Tyr Ile Val Ile Leu Asp 145 150 155 160 Ala Leu Lys Ser His Ser Lys Glu Gly Arg Arg Lys Ala Leu Ser Thr 165 170 175 Cys Val Ser His Ile Thr Val Val Ile Leu Phe Phe Val 180 185 94 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 94 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 95 312 PRT Mus musculus 95 Met Glu Val Asp Ser Asn Ser Ser Ser Gly Thr Phe Ile Leu Met Gly 1 5 10 15 Val Ser Asp His Pro His Leu Glu Ile Ile Phe Phe Ala Val Ile Leu 20 25 30 Ala Ser Tyr Leu Leu Thr Leu Val Gly Asn Leu Thr Ile Ile Leu Leu 35 40 45 Ser Arg Leu Asp Ala Arg Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Ser Leu Asp Leu Ala Phe Thr Thr Ser Ser Val Pro Gln 65 70 75 80 Met Leu Lys Asn Leu Trp Gly Pro Asp Lys Thr Ile Ser Tyr Gly Gly 85 90 95 Cys Val Thr Gln Leu Tyr Val Phe Leu Trp Leu Gly Ala Thr Glu Cys 100 105 110 Ile Leu Leu Val Val Met Ala Phe Asp Arg Tyr Val Ala Val Cys Arg 115 120 125 Pro Leu His Tyr Met Thr Val Met Asn Pro Arg Leu Cys Trp Gly Leu 130 135 140 Ala Ala Ile Ser Trp Leu Gly Gly Leu Gly Asn Ser Val Ile Gln Ser 145 150 155 160 Thr Phe Thr Leu Gln Leu Pro Phe Cys Gly His Arg Lys Val Asp Asn 165 170 175 Phe Leu Cys Glu Val Pro Ala Met Ile Lys Leu Ala Cys Gly Asp Thr 180 185 190 Ser Leu Asn Glu Ala Val Leu Asn Gly Val Cys Thr Phe Phe Thr Val 195 200 205 Val Pro Val Ser Val Ile Leu Val Ser Tyr Cys Phe Ile Ala Gln Ala 210 215 220 Val Met Lys Ile Arg Ser Val Glu Gly Arg Arg Lys Ala Phe Asn Thr 225 230 235 240 Cys Val Ser His Leu Val Val Val Phe Leu Phe Tyr Gly Ser Ala Ile 245 250 255 Tyr Gly Tyr Leu Leu Pro Ala Lys Ser Ser Asn Gln Ser Gln Gly Lys 260 265 270 Phe Ile Ser Leu Phe Tyr Ser Val Val Thr Pro Met Val Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Gly Ala Leu Gly Arg Leu 290 295 300 Leu Gly Lys Gly Arg Gly Ala Ser 305 310 96 320 PRT Homo sapiens 96 Met Asp Gln Ser Asn Tyr Ser Ser Leu His Gly Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asn His Pro Lys Met Glu Met Ile Leu Ser Gly Val Val Ala 20 25 30 Ile Phe Tyr Leu Ile Thr Leu Val Gly Asn Thr Ala Ile Ile Leu Ala 35 40 45 Ser Leu Leu Asp Ser Gln Leu His Thr Pro Met Tyr Phe Phe Leu Arg 50 55 60 Asn Leu Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Ile Ile Pro Gln 65 70 75 80 Met Leu Val Asn Leu Trp Gly Pro Asp Lys Thr Ile Ser Tyr Val Gly 85 90 95 Cys Ile Ile Gln Leu Tyr Val Tyr Met Trp Leu Gly Ser Val Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Ser Tyr Asp Arg Phe Thr Ala Ile Cys Lys 115 120 125 Pro Leu His Tyr Phe Val Val Met Asn Pro His Leu Cys Leu Lys Met 130 135 140 Ile Ile Met Ile Trp Ser Ile Ser Leu Ala Asn Ser Val Val Leu Cys 145 150 155 160 Thr Leu Thr Leu Asn Leu Pro Thr Cys Gly Asn Asn Ile Leu Asp His 165 170 175 Phe Leu Cys Glu Leu Pro Ala Leu Val Lys Ile Ala Cys Val Asp Thr 180 185 190 Thr Thr Val Glu Met Ser Val Phe Ala Leu Gly Ile Ile Ile Val Leu 195 200 205 Thr Pro Leu Ile Leu Ile Leu Ile Ser Tyr Gly Tyr Ile Ala Lys Ala 210 215 220 Val Leu Arg Thr Lys Ser Lys Ala Ser Gln Arg Lys Ala Met Asn Thr 225 230 235 240 Cys Gly Ser His Leu Thr Val Val Ser Met Phe Tyr Gly Thr Ile Ile 245 250 255 Tyr Met Tyr Leu Gln Pro Gly Asn Arg Ala Ser Lys Asp Gln Gly Lys 260 265 270 Phe Leu Thr Leu Phe Tyr Thr Val Ile Thr Pro Ser Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Asp Met Lys Asp Ala Leu Lys Lys Leu 290 295 300 Met Arg Phe His His Lys Ser Thr Lys Ile Lys Arg Asn Cys Lys Ser 305 310 315 320 97 320 PRT Homo sapiens 97 Met Asp Gln Ser Asn Tyr Ser Ser Leu His Gly Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asn His Pro Lys Met Glu Met Ile Leu Ser Gly Val Val Ala 20 25 30 Ile Phe Tyr Leu Ile Thr Leu Val Gly Asn Thr Ala Ile Ile Leu Ala 35 40 45 Ser Leu Leu Asp Ser Gln Leu His Thr Pro Met Tyr Phe Phe Leu Arg 50 55 60 Asn Leu Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Ile Ile Pro Gln 65 70 75 80 Val Leu Val Asn Leu Trp Gly Pro Asp Lys Thr Ile Ser Tyr Val Gly 85 90 95 Cys Ile Ile Gln Leu Tyr Val Tyr Met Trp Leu Gly Ser Val Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Ser Tyr Asp Arg Phe Thr Ala Ile Cys Lys 115 120 125 Pro Leu His Tyr Phe Val Val Met Asn Pro His Leu Cys Leu Lys Met 130 135 140 Ile Ile Met Ile Trp Ser Ile Ser Leu Ala Asn Ser Val Val Leu Cys 145 150 155 160 Thr Leu Thr Leu Asn Leu Pro Thr Cys Gly Asn Asn Ile Leu Asp His 165 170 175 Phe Leu Cys Glu Leu Pro Ala Leu Val Lys Ile Ala Cys Val Asp Thr 180 185 190 Thr Thr Val Glu Met Ser Val Phe Ala Leu Gly Ile Ile Ile Val Leu 195 200 205 Thr Pro Leu Ile Leu Ile Leu Ile Ser Tyr Gly Tyr Ile Ala Lys Ala 210 215 220 Val Leu Arg Thr Lys Ser Lys Ala Ser Gln Arg Lys Ala Met Asn Thr 225 230 235 240 Cys Gly Ser His Leu Thr Val Val Ser Met Phe Tyr Gly Thr Ile Ile 245 250 255 Tyr Met Tyr Leu Gln Pro Gly Asn Arg Ala Ser Lys Asp Gln Gly Lys 260 265 270 Phe Leu Thr Leu Phe Tyr Thr Val Ile Thr Pro Ser Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Asp Met Lys Asp Ala Leu Lys Lys Leu 290 295 300 Met Arg Phe His His Lys Ser Thr Lys Ile Lys Arg Asn Cys Lys Ser 305 310 315 320 98 312 PRT Homo sapiens 98 Met Leu Met Lys Lys Asn Ala Ser Phe Glu Asp Phe Phe Ile Leu Leu 1 5 10 15 Gly Phe Ser Asn Trp Pro His Leu Glu Val Val Leu Phe Val Val Ile 20 25 30 Leu Ile Phe Tyr Leu Ile Thr Leu Ile Gly Asn Leu Phe Ile Ile Ile 35 40 45 Leu Ser Tyr Leu Asp Ser His Leu His Thr Pro Met Tyr Phe Phe Leu 50 55 60 Ser Asn Leu Ser Phe Leu Asp Leu Cys Tyr Thr Thr Ser Ser Ile Pro 65 70 75 80 Gln Leu Leu Val Asn Leu Trp Gly Pro Glu Lys Thr Ile Ser Tyr Ala 85 90 95 Gly Cys Thr Val Gln Leu Tyr Phe Val Leu Ala Leu Gly Thr Ala Glu 100 105 110 Cys Val Leu Leu Val Val Met Ser Tyr Asp Arg Tyr Ala Ala Val Cys 115 120 125 Arg Pro Leu His Tyr Thr Val Leu Met His Pro Arg Phe Cys Arg Leu 130 135 140 Leu Ala Ala Ala Ser Trp Val Ser Gly Phe Thr Thr Ser Ala Leu His 145 150 155 160 Ser Ser Phe Thr Phe Trp Ile Pro Leu Cys Arg His Arg Leu Val Asp 165 170 175 His Phe Phe Cys Glu Val Pro Ala Leu Leu Arg Leu Ser Cys Val Asp 180 185 190 Thr Gln Ala Asn Glu Leu Thr Leu Met Val Met Ser Ser Ile Phe Val 195 200 205 Leu Ile Pro Leu Ile Leu Ile Leu Thr Ser Tyr Gly Ala Ile Ala Arg 210 215 220 Ala Val Leu Ser Met Gln Ser Thr Thr Gly Leu Gln Lys Val Leu Arg 225 230 235 240 Thr Cys Gly Ala His Leu Met Val Val Ser Leu Phe Phe Ile Pro Val 245 250 255 Met Cys Met Tyr Leu Gln Pro Pro Ser Glu Asn Ser Gln Asp Gln Gly 260 265 270 Lys Phe Ile Ala Leu Phe Tyr Thr Val Val Thr Pro Ser Leu Asn Pro 275 280 285 Leu Ile Tyr Thr Phe Arg Asn Lys Asp Val Arg Gly Ala Val Lys Arg 290 295 300 Leu Met Gly Trp Glu Trp Gly Met 305 310 99 320 PRT Homo sapiens 99 Met Asp Gln Ser Asn Tyr Ser Ser Leu His Gly Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asn His Pro Lys Met Glu Met Ile Leu Ser Gly Val Val Ala 20 25 30 Ile Phe Tyr Leu Ile Thr Leu Val Gly Asn Thr Ala Ile Ile Leu Ala 35 40 45 Ser Leu Leu Asp Ser Gln Leu His Thr Pro Met Tyr Phe Phe Leu Arg 50 55 60 Asn Leu Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Ile Ile Pro Gln 65 70 75 80 Met Leu Val Asn Leu Trp Gly Pro Asp Lys Thr Ile Ser Tyr Val Gly 85 90 95 Cys Ile Ile Gln Leu Tyr Val Tyr Met Trp Leu Gly Ser Val Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Ser Tyr Asp Arg Phe Thr Ala Ile Cys Lys 115 120 125 Pro Leu His Tyr Phe Val Val Met Asn Pro His Leu Cys Leu Lys Met 130 135 140 Ile Ile Met Ile Trp Ser Ile Ser Leu Ala Asn Ser Val Val Leu Cys 145 150 155 160 Thr Leu Thr Leu Asn Leu Pro Thr Cys Gly Asn Asn Ile Leu Asp His 165 170 175 Phe Leu Cys Glu Leu Pro Ala Leu Val Lys Ile Ala Cys Val Asp Thr 180 185 190 Thr Thr Val Glu Met Ser Val Phe Ala Leu Gly Ile Ile Ile Val Leu 195 200 205 Thr Pro Leu Ile Leu Ile Leu Ile Ser Tyr Gly Tyr Ile Ala Lys Ala 210 215 220 Val Leu Arg Thr Lys Ser Lys Ala Ser Gln Arg Lys Ala Met Asn Thr 225 230 235 240 Cys Gly Ser His Leu Thr Val Val Ser Met Phe Tyr Gly Thr Ile Ile 245 250 255 Tyr Met Tyr Leu Gln Pro Gly Asn Arg Ala Ser Lys Asp Gln Gly Lys 260 265 270 Phe Leu Thr Leu Phe Tyr Thr Val Ile Thr Pro Ser Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Asn Met Lys Asp Ala Leu Lys Lys Leu 290 295 300 Met Arg Phe His His Lys Ser Thr Lys Ile Lys Arg Asn Cys Lys Ser 305 310 315 320 100 254 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 100 Gly Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg 1 5 10 15 Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu 20 25 30 Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly 35 40 45 Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe 50 55 60 Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile 65 70 75 80 Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg 85 90 95 Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala 100 105 110 Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val 115 120 125 Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser 130 135 140 Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu 145 150 155 160 Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu 165 170 175 Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser 180 185 190 Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val 195 200 205 Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys 210 215 220 Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu 225 230 235 240 Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 101 311 PRT Homo sapiens 101 Met Glu Glu Tyr Asn Thr Ser Ser Thr Asp Phe Thr Phe Met Gly Leu 1 5 10 15 Phe Asn Arg Lys Glu Thr Ser Gly Leu Ile Phe Ala Ile Ile Ser Ile 20 25 30 Ile Phe Phe Thr Ala Leu Met Ala Asn Gly Val Met Ile Phe Leu Ile 35 40 45 Gln Thr Asp Leu Arg Leu His Thr Pro Met Tyr Phe Leu Leu Ser His 50 55 60 Leu Ser Leu Ile Asp Met Met Tyr Ile Ser Thr Ile Val Pro Lys Met 65 70 75 80 Leu Val Asn Tyr Leu Leu Asp Gln Arg Thr Ile Ser Phe Val Gly Cys 85 90 95 Thr Ala Gln His Phe Leu Tyr Leu Thr Leu Val Gly Ala Glu Phe Phe 100 105 110 Leu Leu Gly Leu Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro 115 120 125 Leu Arg Tyr Pro Val Leu Met Ser Arg Arg Val Cys Trp Met Ile Ile 130 135 140 Ala Gly Ser Trp Phe Gly Gly Ser Leu Asp Gly Phe Leu Leu Thr Pro 145 150 155 160 Ile Thr Met Ser Phe Pro Phe Cys Asn Ser Arg Glu Ile Asn His Phe 165 170 175 Phe Cys Glu Ala Pro Ala Val Leu Lys Leu Ala Cys Ala Asp Thr Ala 180 185 190 Leu Tyr Glu Thr Val Met Tyr Val Cys Cys Val Leu Met Leu Leu Ile 195 200 205 Pro Phe Ser Val Val Leu Ala Ser Tyr Ala Arg Ile Leu Thr Thr Val 210 215 220 Gln Cys Met Ser Ser Val Glu Gly Arg Lys Lys Ala Phe Ala Thr Cys 225 230 235 240 Ser Ser His Met Thr Val Val Ser Leu Phe Tyr Gly Ala Ala Met Tyr 245 250 255 Thr Tyr Met Leu Pro His Ser Tyr His Lys Pro Ala Gln Asp Lys Val 260 265 270 Leu Ser Val Phe Tyr Thr Ile Leu Thr Pro Met Leu Asn Pro Leu Ile 275 280 285 Tyr Ser Leu Arg Asn Lys Asp Val Thr Gly Ala Leu Lys Arg Ala Leu 290 295 300 Gly Arg Phe Lys Gly Pro Gln 305 310 102 223 PRT Mus musculus 102 Ser His Leu Ser Phe Ile Asp Met Met Tyr Ile Ser Thr Ile Val Pro 1 5 10 15 Lys Met Leu Val Asp Tyr Leu Leu Gly Gln Arg Thr Ile Ser Phe Val 20 25 30 Gly Cys Thr Ala Gln His Phe Leu Tyr Leu Thr Leu Val Gly Ala Glu 35 40 45 Phe Phe Leu Leu Gly Leu Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys 50 55 60 Asn Pro Leu Arg Tyr Pro Val Leu Met Ser Arg Arg Ile Cys Trp Ile 65 70 75 80 Ile Ile Ala Gly Ser Trp Phe Gly Gly Ser Leu Asp Gly Phe Leu Leu 85 90 95 Thr Pro Ile Thr Met Ser Phe Pro Phe Cys Arg Ser Arg Glu Ile Asn 100 105 110 His Phe Phe Cys Glu Ala Pro Ala Val Leu Lys Leu Ala Cys Ala Asp 115 120 125 Thr Ala Leu Tyr Glu Thr Val Met Tyr Val Cys Cys Val Leu Met Leu 130 135 140 Leu Ile Pro Phe Ser Val Val Ile Ser Ser Tyr Ala Arg Ile Leu Ala 145 150 155 160 Thr Val Tyr His Met Ser Ser Val Glu Gly Arg Lys Lys Ala Phe Ala 165 170 175 Thr Cys Ser Ser His Met Thr Val Val Thr Leu Phe Tyr Gly Ala Ala 180 185 190 Ile Tyr Thr Tyr Met Val Pro His Ser Tyr His Ser Pro Ser Gln Asp 195 200 205 Lys Ile Phe Ser Val Phe Tyr Thr Ile Leu Thr Pro Met Leu Asn 210 215 220 103 216 PRT Homo sapiens 103 Leu Ile Asp Met Met Tyr Ile Ser Thr Ile Val Pro Lys Met Leu Val 1 5 10 15 Asn Tyr Leu Leu Asp Gln Arg Thr Ile Ser Phe Val Gly Cys Thr Ala 20 25 30 Gln His Phe Leu Tyr Leu Thr Leu Val Gly Ala Glu Phe Phe Leu Leu 35 40 45 Gly Leu Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys Asn Pro Leu Arg 50 55 60 Tyr Pro Val Leu Met Ser Arg Arg Val Cys Trp Met Ile Ile Ala Gly 65 70 75 80 Ser Trp Phe Gly Gly Ser Leu Asp Gly Phe Leu Leu Thr Pro Ile Thr 85 90 95 Met Ser Phe Pro Phe Cys Asn Ser Arg Glu Ile Asn His Phe Phe Cys 100 105 110 Glu Ala Pro Ala Val Leu Lys Leu Ala Cys Ala Asp Thr Ala Leu Tyr 115 120 125 Glu Thr Val Met Tyr Val Cys Cys Val Leu Met Leu Leu Ile Pro Phe 130 135 140 Ser Val Val Leu Ala Ser Tyr Ala Arg Ile Leu Thr Thr Val Gln Cys 145 150 155 160 Met Ser Ser Val Glu Gly Arg Lys Lys Ala Phe Ala Thr Cys Ser Ser 165 170 175 His Met Thr Val Val Ser Leu Phe Tyr Gly Ala Ala Met Tyr Thr Tyr 180 185 190 Met Leu Pro His Ser Tyr His Lys Pro Ala Gln Asp Lys Val Leu Ser 195 200 205 Val Phe Tyr Thr Ile Leu Thr Pro 210 215 104 316 PRT Mus musculus 104 Met Glu Pro Trp Asn Ser Thr Leu Gly Thr Asp Phe Asn Leu Val Gly 1 5 10 15 Ile Leu Asp Asp Ser Gly Ser Pro Glu Leu Leu Cys Ala Thr Phe Thr 20 25 30 Ala Leu Tyr Met Leu Ala Leu Ile Ser Asn Gly Leu Leu Ile Leu Val 35 40 45 Ile Thr Met Asp Ala Arg Leu His Val Pro Met Tyr Phe Leu Leu Gly 50 55 60 Gln Leu Ser Leu Met Asp Leu Leu Phe Thr Ser Val Val Thr Pro Lys 65 70 75 80 Ala Val Ile Asp Phe Leu Leu Arg Asp Asn Thr Ile Ser Phe Glu Gly 85 90 95 Cys Ser Leu Gln Met Phe Leu Ala Leu Thr Leu Gly Gly Ala Glu Asp 100 105 110 Leu Leu Leu Ala Phe Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Asn Tyr Met Ile Phe Met Arg Pro Ser Ile Cys Trp Leu Met 130 135 140 Val Ala Thr Ser Trp Val Leu Ala Ser Leu Met Ala Leu Gly Tyr Thr 145 150 155 160 Thr Tyr Thr Met Gln Tyr Ser Tyr Cys Lys Ser Arg Lys Ile Arg His 165 170 175 Leu Leu Cys Glu Ile Pro Pro Leu Leu Lys Leu Ala Cys Ala Asp Thr 180 185 190 Ser Lys Tyr Glu Leu Met Val Tyr Val Met Gly Val Thr Phe Leu Ile 195 200 205 Pro Pro Leu Ala Ala Ile Leu Ala Ser Tyr Ser Leu Ile Leu Phe Thr 210 215 220 Val Leu His Met Pro Ser Asn Glu Gly Arg Lys Lys Ala Leu Val Thr 225 230 235 240 Cys Ser Ser His Leu Thr Val Val Gly Met Phe Tyr Gly Ala Ala Thr 245 250 255 Phe Met Tyr Val Leu Pro Asn Ser Phe His Ser Pro Arg Gln Asp Asn 260 265 270 Ile Ile Ser Val Phe Tyr Thr Ile Val Thr Pro Ala Leu Asn Pro Leu 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Glu Val Thr Gly Ala Leu Ile Arg Val 290 295 300 Leu Gly Arg Tyr Ile Val Pro Ala His Pro Thr Leu 305 310 315 105 315 PRT Mus musculus 105 Met Glu Val Cys Asn Ser Thr Leu Arg Ser Gly Phe Ile Leu Met Gly 1 5 10 15 Ile Leu Asp Asp Asn Asp Phe Pro Glu Leu Leu Cys Ala Thr Ile Thr 20 25 30 Ala Leu Tyr Leu Leu Ala Leu Thr Ser Asn Gly Leu Leu Leu Leu Val 35 40 45 Ile Thr Met Asp Thr Arg Leu His Val Pro Met Tyr Leu Leu Leu Trp 50 55 60 Gln Leu Ser Leu Met Asp Leu Leu Leu Thr Ser Val Ile Thr Pro Lys 65 70 75 80 Ala Ile Leu Asp Tyr Leu Leu Lys Asp Asn Thr Ile Ser Phe Gly Gly 85 90 95 Cys Ala Leu Gln Met Phe Leu Ala Leu Thr Leu Gly Thr Ala Glu Asp 100 105 110 Leu Leu Leu Ser Phe Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Asn Tyr Thr Ile Leu Met Ser Gln Lys Val Cys Cys Leu Met 130 135 140 Ile Ala Thr Ser Trp Ser Leu Ala Ser Leu Ser Ala Leu Gly Tyr Ser 145 150 155 160 Met Tyr Thr Met Gln Tyr Pro Phe Cys Lys Ser Arg Gln Ile Arg His 165 170 175 Leu Phe Cys Glu Ile Pro Pro Leu Leu Lys Leu Ala Cys Ala Asp Thr 180 185 190 Ser Thr Tyr Glu Leu Met Val Tyr Leu Met Gly Val Thr Leu Leu Phe 195 200 205 Pro Ala Leu Ala Ala Ile Leu Ala Ser Tyr Ser Leu Ile Leu Phe Thr 210 215 220 Val Leu His Met Pro Ser Asn Glu Gly Arg Arg Lys Ala Leu Val Thr 225 230 235 240 Cys Ser Ser His Leu Thr Val Val Gly Met Trp Tyr Gly Gly Ala Ile 245 250 255 Val Met Tyr Val Leu Pro Ser Ser Phe His Ser Pro Lys Gln Asp Asn 260 265 270 Ile Ser Ser Val Phe Tyr Thr Ile Phe Thr Pro Ala Leu Asn Pro Leu 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Glu Val Thr Gly Ala Leu Arg Arg Val 290 295 300 Leu Gly Lys Arg Leu Ser Val Gln Ser Thr Phe 305 310 315 106 253 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 106 Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg Thr 1 5 10 15 Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu Phe 20 25 30 Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly Asp 35 40 45 Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe Val 50 55 60 Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile Asp 65 70 75 80 Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg Thr 85 90 95 Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala Leu 100 105 110 Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val Glu 115 120 125 Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser Val 130 135 140 Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu Pro 145 150 155 160 Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu Arg 165 170 175 Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser Glu 180 185 190 Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val Leu 195 200 205 Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys Leu 210 215 220 Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu Trp 225 230 235 240 Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 107 312 PRT Mus musculus 107 Met Glu Val Asp Ser Asn Ser Ser Ser Gly Thr Phe Ile Leu Met Gly 1 5 10 15 Val Ser Asp His Pro His Leu Glu Ile Ile Phe Phe Ala Val Ile Leu 20 25 30 Ala Ser Tyr Leu Leu Thr Leu Val Gly Asn Leu Thr Ile Ile Leu Leu 35 40 45 Ser Arg Leu Asp Ala Arg Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Ser Leu Asp Leu Ala Phe Thr Thr Ser Ser Val Pro Gln 65 70 75 80 Met Leu Lys Asn Leu Trp Gly Pro Asp Lys Thr Ile Ser Tyr Gly Gly 85 90 95 Cys Val Thr Gln Leu Tyr Val Phe Leu Trp Leu Gly Ala Thr Glu Cys 100 105 110 Ile Leu Leu Val Val Met Ala Phe Asp Arg Tyr Val Ala Val Cys Arg 115 120 125 Pro Leu His Tyr Met Thr Val Met Asn Pro Arg Leu Cys Trp Gly Leu 130 135 140 Ala Ala Ile Ser Trp Leu Gly Gly Leu Gly Asn Ser Val Ile Gln Ser 145 150 155 160 Thr Phe Thr Leu Gln Leu Pro Phe Cys Gly His Arg Lys Val Asp Asn 165 170 175 Phe Leu Cys Glu Val Pro Ala Met Ile Lys Leu Ala Cys Gly Asp Thr 180 185 190 Ser Leu Asn Glu Ala Val Leu Asn Gly Val Cys Thr Phe Phe Thr Val 195 200 205 Val Pro Val Ser Val Ile Leu Val Ser Tyr Cys Phe Ile Ala Gln Ala 210 215 220 Val Met Lys Ile Arg Ser Val Glu Gly Arg Arg Lys Ala Phe Asn Thr 225 230 235 240 Cys Val Ser His Leu Val Val Val Phe Leu Phe Tyr Gly Ser Ala Ile 245 250 255 Tyr Gly Tyr Leu Leu Pro Ala Lys Ser Ser Asn Gln Ser Gln Gly Lys 260 265 270 Phe Ile Ser Leu Phe Tyr Ser Val Val Thr Pro Met Val Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Gly Ala Leu Gly Arg Leu 290 295 300 Leu Gly Lys Gly Arg Gly Ala Ser 305 310 108 313 PRT Rattus norvegicus 108 Met Ser Val Ala Asn Glu Ser Ile Ser Arg Glu Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asp Arg Pro Trp Leu Glu Leu Pro Leu Phe Val Val Phe Leu 20 25 30 Val Ser Tyr Ile Leu Thr Ile Phe Gly Asn Met Met Ile Ile Leu Val 35 40 45 Ser Arg Leu Asp Ser Lys Leu His Thr Pro Met Tyr Phe Phe Leu Thr 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Ile Asn Ile Cys Ser Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Val Gln Leu Phe Ile Phe Leu Ser Leu Gly Ser Thr Glu Cys 100 105 110 Phe Leu Leu Gly Val Met Ser Leu Asp Arg Phe Leu Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Val Ile Met His Gln Arg Arg Cys Leu His Leu 130 135 140 Ala Ala Ala Cys Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Gln Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Lys Ile Arg Ser Ala Glu Cys Arg Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Val Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Tyr Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Tyr Gly Ile Ile Thr Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Glu Glu Val Lys Gly Ala Phe Lys Arg Leu 290 295 300 Met Lys Arg Ile Ile Leu Ile Gly Lys 305 310 109 357 PRT Homo sapiens 109 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Arg Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu Asn Gln Glu Ile Arg Asn Met Gln Met Ile 305 310 315 320 Ser Phe Ala Lys Asp Thr Val Leu Thr Tyr Leu Thr Asn Phe Ser Ala 325 330 335 Ser Cys Pro Ile Phe Val Ile Thr Ile Glu Asn Tyr Cys Asn Leu Pro 340 345 350 Gln Arg Lys Phe Pro 355 110 316 PRT Homo sapiens 110 Met Asp Asn Gln Ser Ser Thr Pro Gly Phe Leu Leu Leu Gly Phe Ser 1 5 10 15 Glu His Pro Gly Leu Glu Arg Thr Leu Phe Val Val Val Phe Thr Ser 20 25 30 Tyr Leu Leu Thr Leu Val Gly Asn Thr Leu Ile Ile Leu Leu Ser Ala 35 40 45 Leu Asp Pro Lys Leu His Ser Pro Met Tyr Phe Phe Leu Ser Asn Leu 50 55 60 Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Cys Val Pro Gln Met Leu 65 70 75 80 Val Asn Leu Trp Gly Pro Lys Lys Thr Ile Ser Phe Leu Asp Cys Ser 85 90 95 Val Gln Ile Phe Ile Phe Leu Ser Leu Gly Thr Thr Glu Cys Ile Leu 100 105 110 Leu Thr Val Met Ala Phe Asp Arg Tyr Val Ala Val Cys Gln Pro Leu 115 120 125 His Tyr Ala Thr Ile Ile His Pro Arg Leu Cys Trp Gln Leu Ala Ser 130 135 140 Val Ala Trp Val Ile Gly Leu Val Glu Ser Val Val Gln Thr Pro Ser 145 150 155 160 Thr Leu His Leu Pro Phe Cys Pro Asp Arg Gln Val Asp Asp Phe Val 165 170 175 Cys Glu Val Pro Ala Leu Ile Arg Leu Ser Cys Glu Asp Thr Ser Tyr 180 185 190 Asn Glu Ile Gln Val Ala Val Ala Ser Val Phe Ile Leu Val Val Pro 195 200 205 Leu Ser Leu Ile Leu Val Ser Tyr Gly Ala Ile Thr Trp Ala Val Leu 210 215 220 Arg Ile Asn Ser Ala Lys Gly Arg Arg Lys Ala Phe Gly Thr Cys Ser 225 230 235 240 Ser His Leu Thr Val Val Thr Leu Phe Tyr Ser Ser Val Ile Ala Val 245 250 255 Tyr Leu Gln Pro Lys Asn Pro Tyr Ala Gln Glu Arg Gly Lys Phe Phe 260 265 270 Gly Leu Phe Tyr Ala Val Gly Thr Pro Ser Leu Asn Pro Leu Ile Tyr 275 280 285 Thr Leu Arg Asn Lys Glu Val Thr Arg Ala Phe Arg Arg Leu Leu Gly 290 295 300 Lys Glu Arg Asp Ser Arg Glu Ser Trp Arg Ala Ala 305 310 315 111 357 PRT Homo sapiens 111 Met Asn Trp Val Asn Lys Ser Val Pro Gln Glu Phe Ile Leu Leu Val 1 5 10 15 Phe Ser Asp Gln Pro Trp Leu Glu Ile Pro Pro Phe Val Met Phe Leu 20 25 30 Phe Ser Tyr Ile Leu Thr Ile Phe Gly Asn Leu Thr Ile Ile Leu Val 35 40 45 Ser His Val Asp Phe Lys Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Leu Leu Asp Leu Cys Tyr Thr Thr Ser Thr Val Pro Gln 65 70 75 80 Met Leu Val Asn Ile Cys Asn Thr Arg Lys Val Ile Ser Tyr Gly Gly 85 90 95 Cys Val Ala Gln Leu Phe Ile Phe Leu Ala Leu Gly Ser Thr Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Cys Phe Asp Arg Phe Val Ala Ile Cys Arg 115 120 125 Pro Leu His Tyr Ser Ile Ile Met His Gln Arg Leu Cys Phe Gln Leu 130 135 140 Ala Ala Ala Ser Trp Ile Ser Gly Phe Ser Asn Ser Val Leu Gln Ser 145 150 155 160 Thr Trp Thr Leu Lys Met Pro Leu Cys Gly His Lys Glu Val Asp His 165 170 175 Phe Phe Cys Glu Val Pro Ala Leu Leu Lys Leu Ser Cys Val Asp Thr 180 185 190 Thr Ala Asn Glu Ala Glu Leu Phe Phe Ile Ser Val Leu Phe Leu Leu 195 200 205 Ile Pro Val Thr Leu Ile Leu Ile Ser Tyr Ala Phe Ile Val Gln Ala 210 215 220 Val Leu Arg Ile Gln Ser Ala Glu Gly Gln Arg Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Ile Val Val Ser Leu Phe Tyr Gly Thr Ala Ile 245 250 255 Ser Met Tyr Leu Gln Pro Pro Ser Pro Ser Ser Lys Asp Arg Gly Lys 260 265 270 Met Val Ser Leu Phe Cys Gly Ile Ile Ala Pro Met Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Glu Val Lys Glu Ala Phe Lys Arg Leu 290 295 300 Val Ala Lys Ser Leu Leu Asn Gln Glu Ile Arg Asn Met Gln Met Ile 305 310 315 320 Ser Phe Ala Lys Asp Thr Val Leu Thr Tyr Leu Thr Asn Phe Ser Ala 325 330 335 Ser Cys Pro Ile Phe Val Ile Thr Ile Glu Asn Tyr Cys Asn Leu Pro 340 345 350 Gln Arg Lys Phe Pro 355 112 241 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 112 Lys Leu Arg Thr Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala 1 5 10 15 Asp Leu Leu Phe Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu 20 25 30 Val Gly Gly Asp Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly 35 40 45 Ala Leu Phe Val Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala 50 55 60 Ile Ser Ile Asp Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg 65 70 75 80 Arg Ile Arg Thr Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp 85 90 95 Val Leu Ala Leu Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu 100 105 110 Arg Thr Val Glu Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro 115 120 125 Glu Glu Ser Val Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly 130 135 140 Phe Val Leu Pro Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu 145 150 155 160 Arg Thr Leu Arg Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg 165 170 175 Ser Ser Ser Glu Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val 180 185 190 Val Phe Val Leu Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp 195 200 205 Ser Leu Cys Leu Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu 210 215 220 Ile Thr Leu Trp Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile 225 230 235 240 Tyr 113 321 PRT Homo sapiens 113 Met Glu Arg Lys Asn Gln Thr Ala Ile Thr Glu Phe Ile Ile Leu Gly 1 5 10 15 Phe Ser Asn Leu Asn Glu Leu Gln Phe Leu Leu Phe Thr Ile Phe Phe 20 25 30 Leu Thr Tyr Phe Cys Thr Leu Gly Gly Asn Ile Leu Ile Ile Leu Thr 35 40 45 Thr Val Thr Asp Pro His Leu His Thr Pro Met Tyr Tyr Phe Leu Gly 50 55 60 Asn Leu Ala Phe Ile Asp Ile Cys Tyr Thr Thr Ser Asn Val Pro Gln 65 70 75 80 Met Met Val His Leu Leu Ser Lys Lys Lys Ser Ile Ser Tyr Val Gly 85 90 95 Cys Val Val Gln Leu Phe Ala Phe Val Phe Phe Val Gly Ser Glu Cys 100 105 110 Leu Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Ile Ala Ile Cys Asn 115 120 125 Pro Leu Arg Tyr Ser Val Ile Leu Ser Lys Val Leu Cys Asn Gln Leu 130 135 140 Ala Ala Ser Cys Trp Ala Ala Gly Phe Leu Asn Ser Val Val His Thr 145 150 155 160 Val Leu Thr Phe Cys Leu Pro Phe Cys Gly Asn Asn Gln Ile Asn Tyr 165 170 175 Phe Phe Cys Asp Ile Pro Pro Leu Leu Ile Leu Ser Cys Gly Asn Thr 180 185 190 Ser Val Asn Glu Leu Ala Leu Leu Ser Thr Gly Val Phe Ile Gly Trp 195 200 205 Thr Pro Phe Leu Cys Ile Val Leu Ser Tyr Ile Cys Ile Ile Ser Thr 210 215 220 Ile Leu Arg Ile Gln Ser Ser Glu Gly Arg Arg Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Ala Ile Val Phe Leu Phe Tyr Gly Ser Ala Ile 245 250 255 Phe Thr Tyr Val Arg Pro Ile Ser Thr Tyr Ser Leu Lys Lys Asp Arg 260 265 270 Leu Val Ser Val Leu Tyr Ser Val Val Thr Pro Met Leu Asn Pro Ile 275 280 285 Ile Tyr Thr Leu Arg Asn Lys Asp Ile Lys Glu Ala Val Lys Thr Ile 290 295 300 Gly Ser Lys Trp Gln Pro Pro Ile Ser Ser Leu Asp Ser Lys Leu Thr 305 310 315 320 Tyr 114 327 PRT Mus musculus 114 Met Glu Arg Arg Asn His Thr Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Ala Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Ala Tyr Val Leu Val Leu Thr Glu Asn Ile Leu Ile Ile Thr 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Glu Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Ile Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Leu Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Glu Val Lys Lys 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Gly Gln Asp Ala Asn Thr 305 310 315 320 Lys Lys Ser Ser Arg Asp Gly 325 115 314 PRT Mus musculus 115 Met Leu Asp Met Asn Ile Thr Leu Val Ser Glu Phe Ile Leu Val Gly 1 5 10 15 Phe Pro Thr Ala Pro Trp Leu Gln Ile Leu Leu Phe Phe Ile Phe Leu 20 25 30 Val Val Tyr Met Leu Ile Ile Ala Glu Asn Leu Val Ile Ile Phe Thr 35 40 45 Val Trp Ser Thr Gly Ser Leu His Lys Pro Met Tyr Tyr Phe Leu Ser 50 55 60 Ser Met Ser Phe Leu Glu Ile Trp Tyr Val Ser Val Thr Val Pro Lys 65 70 75 80 Met Leu Asp Gly Phe Leu Leu Gln Arg Arg His Ile Ser Phe Thr Gly 85 90 95 Cys Met Thr Gln Leu Tyr Phe Phe Ile Ser Leu Ala Cys Thr Glu Cys 100 105 110 Val Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Pro Val Ile Met Thr Thr Val Tyr Cys Met Gln Leu 130 135 140 Met Ala Leu Ser Tyr Phe Ser Gly Phe Met Val Ser Val Val Lys Val 145 150 155 160 Tyr Phe Ile Ser His Val Ala Phe Cys Gly Ser Asn Val Met Asn His 165 170 175 Phe Phe Cys Asp Ile Ser Pro Ile Leu Lys Leu Ala Cys Lys Asp Met 180 185 190 Ser Thr Ala Glu Leu Val Asp Phe Ala Leu Ala Ile Val Ile Leu Val 195 200 205 Phe Pro Leu Ile Thr Thr Val Leu Ser Tyr Val Tyr Ile Val Ser Thr 210 215 220 Ile Leu Arg Ile Pro Ser Thr Gln Gly Arg Lys Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Thr Val Val Ile Ile Tyr Tyr Thr Ala Met Ile 245 250 255 Phe Met Tyr Val Arg Pro Arg Ala Ile Ala Ser Phe Asn Ser Asn Lys 260 265 270 Leu Ile Ser Ala Val Tyr Ala Val Leu Thr Pro Met Leu Asn Pro Phe 275 280 285 Ile Tyr Cys Leu Arg Asn Arg Glu Val Lys Asp Ala Ile Lys Lys Thr 290 295 300 Leu Gly Gly Gly Gln Cys Phe Leu Leu Cys 305 310 116 327 PRT Rattus norvegicus VARIANT (35) Where Xaa is Asp, Val, Ser or Gly 116 Met Glu Arg Arg Asn His Ser Gly Arg Val Ser Glu Phe Val Leu Leu 1 5 10 15 Gly Phe Pro Ala Pro Ala Pro Leu Arg Val Leu Leu Phe Phe Leu Ser 20 25 30 Leu Leu Xaa Tyr Val Leu Val Leu Thr Glu Asn Met Leu Ile Ile Ile 35 40 45 Ala Ile Arg Asn His Pro Thr Leu His Lys Pro Met Tyr Phe Phe Leu 50 55 60 Ala Asn Met Ser Phe Leu Glu Ile Trp Tyr Val Thr Val Thr Ile Pro 65 70 75 80 Lys Met Leu Ala Gly Phe Ile Gly Ser Lys Glu Asn His Gly Gln Leu 85 90 95 Ile Ser Phe Glu Ala Cys Met Thr Gln Leu Tyr Phe Phe Leu Gly Leu 100 105 110 Gly Cys Thr Glu Cys Val Leu Leu Ala Val Met Ala Tyr Asp Arg Tyr 115 120 125 Val Ala Ile Cys His Pro Leu His Tyr Pro Val Ile Val Ser Ser Arg 130 135 140 Leu Cys Val Gln Met Ala Ala Gly Ser Trp Ala Gly Gly Phe Gly Ile 145 150 155 160 Ser Met Val Lys Val Phe Leu Ile Ser Arg Leu Ser Tyr Cys Gly Pro 165 170 175 Asn Thr Ile Asn His Phe Phe Cys Asp Val Ser Pro Leu Leu Asn Leu 180 185 190 Ser Cys Thr Asp Met Ser Thr Ala Glu Leu Thr Asp Phe Val Leu Ala 195 200 205 Ile Phe Ile Leu Leu Gly Pro Leu Ser Val Thr Gly Ala Ser Tyr Met 210 215 220 Ala Ile Thr Gly Ala Val Met Arg Ile Pro Ser Ala Ala Gly Arg His 225 230 235 240 Lys Ala Phe Ser Thr Cys Ala Ser His Leu Thr Val Val Ile Ile Phe 245 250 255 Tyr Ala Ala Ser Ile Phe Ile Tyr Ala Arg Pro Lys Ala Leu Ser Ala 260 265 270 Phe Asp Thr Asn Lys Leu Val Ser Val Leu Tyr Ala Val Ile Val Pro 275 280 285 Leu Phe Asn Pro Ile Ile Tyr Cys Leu Arg Asn Gln Asp Val Lys Arg 290 295 300 Ala Leu Arg Arg Thr Leu His Leu Ala Gln Asp Gln Glu Ala Asn Thr 305 310 315 320 Asn Lys Gly Ser Lys Ile Gly 325 117 317 PRT Mus musculus 117 Met Glu Gly Lys Asn Gln Thr Ala Pro Ser Glu Phe Ile Ile Leu Gly 1 5 10 15 Phe Asp His Leu Asn Glu Leu Gln Tyr Leu Leu Phe Thr Ile Phe Phe 20 25 30 Leu Thr Tyr Ile Cys Thr Leu Gly Gly Asn Val Phe Ile Ile Val Val 35 40 45 Thr Ile Ala Asp Ser His Leu His Thr Pro Met Tyr Tyr Phe Leu Gly 50 55 60 Asn Leu Ala Leu Ile Asp Ile Cys Tyr Thr Thr Thr Asn Val Pro Gln 65 70 75 80 Met Met Val His Leu Leu Ser Glu Lys Lys Ile Ile Ser Tyr Gly Gly 85 90 95 Cys Val Thr Gln Leu Phe Ala Phe Ile Phe Phe Val Gly Ser Glu Cys 100 105 110 Leu Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Ile Ala Ile Cys Lys 115 120 125 Pro Leu Arg Tyr Ser Phe Ile Met Asn Lys Ala Leu Cys Ser Trp Leu 130 135 140 Ala Ala Ser Cys Trp Thr Cys Gly Phe Leu Asn Ser Val Leu His Thr 145 150 155 160 Val Leu Thr Phe His Leu Pro Phe Cys Gly Asn Asn Gln Ile Asn Tyr 165 170 175 Phe Phe Cys Asp Ile Pro Pro Leu Leu Ile Leu Ser Cys Gly Asp Thr 180 185 190 Ser Leu Asn Glu Leu Ala Leu Leu Ser Ile Gly Ile Leu Ile Gly Trp 195 200 205 Thr Pro Phe Leu Cys Ile Ile Leu Ser Tyr Leu Tyr Ile Ile Ser Thr 210 215 220 Ile Leu Arg Ile Arg Ser Ser Glu Gly Arg Gln Lys Ala Phe Ser Thr 225 230 235 240 Cys Ala Ser His Leu Leu Ile Val Ile Leu Tyr Tyr Gly Ser Ala Ile 245 250 255 Phe Thr Tyr Val Arg Pro Ile Ser Ser Tyr Ser Leu Glu Lys Asp Arg 260 265 270 Leu Ile Ser Val Leu Tyr Ser Val Phe Thr Pro Met Leu Asn Pro Ile 275 280 285 Ile Tyr Ala Leu Arg Asn Lys Asp Ile Lys Glu Ala Val Lys Ala Ile 290 295 300 Gly Arg Lys Trp Gln Pro Pro Val Phe Ser Ser Asp Met 305 310 315 118 253 PRT Artificial Sequence Description of Artificial Sequence7tm_1, 7 transmembrane receptor domain sequence 118 Asn Leu Leu Val Ile Leu Val Ile Leu Arg Thr Lys Lys Leu Arg Thr 1 5 10 15 Pro Thr Asn Ile Phe Leu Leu Asn Leu Ala Val Ala Asp Leu Leu Phe 20 25 30 Leu Leu Thr Leu Pro Pro Trp Ala Leu Tyr Tyr Leu Val Gly Gly Asp 35 40 45 Trp Val Phe Gly Asp Ala Leu Cys Lys Leu Val Gly Ala Leu Phe Val 50 55 60 Val Asn Gly Tyr Ala Ser Ile Leu Leu Leu Thr Ala Ile Ser Ile Asp 65 70 75 80 Arg Tyr Leu Ala Ile Val His Pro Leu Arg Tyr Arg Arg Ile Arg Thr 85 90 95 Pro Arg Arg Ala Lys Val Leu Ile Leu Leu Val Trp Val Leu Ala Leu 100 105 110 Leu Leu Ser Leu Pro Pro Leu Leu Phe Ser Trp Leu Arg Thr Val Glu 115 120 125 Glu Gly Asn Thr Thr Val Cys Leu Ile Asp Phe Pro Glu Glu Ser Val 130 135 140 Lys Arg Ser Tyr Val Leu Leu Ser Thr Leu Val Gly Phe Val Leu Pro 145 150 155 160 Leu Leu Val Ile Leu Val Cys Tyr Thr Arg Ile Leu Arg Thr Leu Arg 165 170 175 Lys Arg Ala Arg Ser Gln Arg Ser Leu Lys Arg Arg Ser Ser Ser Glu 180 185 190 Arg Lys Ala Ala Lys Met Leu Leu Val Val Val Val Val Phe Val Leu 195 200 205 Cys Trp Leu Pro Tyr His Ile Val Leu Leu Leu Asp Ser Leu Cys Leu 210 215 220 Leu Ser Ile Trp Arg Val Leu Pro Thr Ala Leu Leu Ile Thr Leu Trp 225 230 235 240 Leu Ala Tyr Val Asn Ser Cys Leu Asn Pro Ile Ile Tyr 245 250 119 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 119 accatcatca agagtgctat gg 22 120 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 120 tcctttcgaa gcttctgcat catcct 26 121 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 121 aggcatgtca gcaagaatac at 22 122 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 122 atggcatttg atcgctatgt ag 22 123 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 123 tgagatatac caccatcttg actccca 27 124 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 124 ccatagcact cttgatgatg gt 22 125 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 125 accatcatca agagtgctat gg 22 126 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 126 tcctttcgaa gcttctgcat catcct 26 127 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 127 aggcatgtca gcaagaatac at 22 128 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 128 ccatggcatt tgatcactat gt 22 129 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 129 tgagatatac caccatcttg actccca 27 130 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 130 ccatagcact cttgatgatg gt 22 131 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 131 ccatggcatt tgatcactat gt 22 132 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 132 tgagatatac caccatcttg actccca 27 133 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 133 ccatagcact cttgatgatg gt 22 134 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 134 atcccactgt gcttcatgta tc 22 135 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 135 atcccgggca actgcacaat tctttt 26 136 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 136 agtgagcgct ctgttttaat ga 22 137 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 137 atcccactgt gcttcatgta tc 22 138 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 138 atcccgggca actgcacaat tctttt 26 139 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 139 agtgagcgct ctgttttaat ga 22 140 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 140 atcccactgt gcttcatgta tc 22 141 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 141 atcccgggca actgcacaat tctttt 26 142 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 142 agtgagcgct ctgttttaat ga 22 143 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 143 ctctcttctg tggaatcatt gc 22 144 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 144 cccatgctga atccccttat atataca 27 145 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 145 ggcttccttt acctctttgt tc 22 146 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 146 agattccacc ctttgtgatg tt 22 147 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 147 tcttgacaat ctttggcaat ctgaca 26 148 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 148 tgaaatccac atgtgacaca ag 22 149 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 149 agattccacc ctttgtgatg tt 22 150 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 150 tcttgacaat ctttggcaat ctgaca 26 151 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 151 tgaaatccac atgtgacaca ag 22 152 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 152 ggaaagtgtc ctccctgttc ta 22 153 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 153 ccataatagt ccccgtgtta aaccca 26 154 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 154 ctttgacatc cttgttcctc aa 22 155 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 155 ggaaagtgtc ctccctgttc ta 22 156 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 156 ccataatagt ccccgtgtta aaccca 26 157 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 157 ctttgacatc cttgttcctc aa 22 158 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 158 cctctccagc attctacaca ac 22 159 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 159 tctacagaag gcaggtccaa agcctt 26 160 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 160 caattatgtg ggaactgcaa gt 22 161 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 161 attccacaca ccttttgtga ac 22 162 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 162 acattggcct agccaaatat gcatgt 26 163 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 163 ggaaaaccca taccaaatgt tt 22 164 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 164 attccacaca ccttttgtga ac 22 165 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 165 acattggcct agccaaatat gcatgt 26 166 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 166 ggaaaaccca taccaaatgt tt 22 167 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 167 caaccagcca cagagatagt tg 22 168 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 168 cttcttgcag gaagccctcc agcatt 26 169 21 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 169 tctctacacc tccgcagtga t 21 170 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 170 gctcaggtga caactctcat tc 22 171 28 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 171 tgtgttctgc ctcactattc cttttgga 28 172 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 172 caccacaatt ctggcataag at 22 173 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 173 gcgcaataga atacgtcaat tt 22 174 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 174 cagctcctaa gcctcttaga ccccaa 26 175 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 175 aaccatgact ccaatctcaa tg 22 176 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 176 taccgatcat agcacatcat ca 22 177 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 177 tcagacactc tgtaatagca aacgcca 27 178 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 178 tgctccttgc atacttcaga ct 22 179 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 179 attctcaaga acggaggaag at 22 180 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 180 tttacagcct tttcaacccg atcctg 26 181 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 181 tctgcattcc taaggctgta ga 22 182 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 182 attctcaaga acggaggaag at 22 183 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 183 tttacagcct tttcaacccg atcctg 26 184 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 184 tctgcattcc taaggctgta ga 22 185 21 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 185 aggaagatcc tttccctgtt t 21 186 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 186 tacagccttt tcaacccgat cctgaa 26 187 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 187 ctctctttag agcccctttc ac 22 188 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 188 catgctgtga ccatcatcat ta 22 189 27 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 189 ccttcctaat cattgccctg tcctatg 27 190 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 190 cttcagaaga gggaatcctc aa 22 191 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 191 gaagaggatc tgtatggttg ca 22 192 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 192 tcctacccat gacactccca ctagca 26 193 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 193 tgcactatac caccatcatg aa 22 194 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 194 ggctgtggtg tctctgtttt ac 22 195 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 195 catcttcatg tatctccagc cagcca 26 196 21 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 196 ctatgaactt gccctgctca t 21 197 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 197 acctcccaac aaccttctgt ag 22 198 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 198 ccgtgacatc cttgttccta aggctg 26 199 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 199 ccatgctcaa tccactcatt ta 22 200 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 200 ctattttggg gaataccacc at 22 201 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 201 tctcgtctgg aacccaagcc tcatat 26 202 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 202 ggaaggagag atgagaaagg aa 22 203 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 203 acgcagtgtt gaggattaag tc 22 204 26 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 204 acagaaagca ttcgggacct gcttct 26 205 22 DNA Artificial Sequence Description of Artificial Sequence PCR Primer Sequence 205 tgatggttcc ataaaagatg gt 22 

What is claimed is:
 1. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; (b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of the amino acid residues from the amino acid sequence of said mature form; (c) an amino acid sequence selected from the group consisting SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; and (d) a variant of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence.
 2. The polypeptide of claim 1, wherein said polypeptide comprises the amino acid sequence of a naturally-occurring allelic variant of an amino acid sequence selected from the group consisting SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and
 34. 3. The polypeptide of claim 2, wherein said allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and
 33. 4. The polypeptide of claim 1, wherein the amino acid sequence of said variant comprises a conservative amino acid substitution.
 5. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; (b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of the amino acid residues from the amino acid sequence of said mature form; (c) an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34; (d) a variant of an amino acid sequence selected from the group consisting SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising an amino acid sequence chosen from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34, or a variant of said polypeptide, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence; and (f) a nucleic acid molecule comprising the complement of (a), (b), (c), (d) or (e).
 6. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally-occurring allelic nucleic acid variant.
 7. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule encodes a polypeptide comprising the amino acid sequence of a naturally-occurring polypeptide variant.
 8. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and
 33. 9. The nucleic acid molecule of claim 5, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33; (b) a nucleotide sequence differing by one or more nucleotides from a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, provided that no more than 20% of the nucleotides differ from said nucleotide sequence; (c) a nucleic acid fragment of (a); and (d) a nucleic acid fragment of (b).
 10. The nucleic acid molecule of claim 5, wherein said nucleic acid molecule hybridizes under stringent conditions to a nucleotide sequence chosen from the group consisting SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, or a complement of said nucleotide sequence.
 11. The nucleic acid molecule of claim 5, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) a first nucleotide sequence comprising a coding sequence differing by one or more nucleotide sequences from a coding sequence encoding said amino acid sequence, provided that no more than 20% of the nucleotides in the coding sequence in said first nucleotide sequence differ from said coding sequence; (b) an isolated second polynucleotide that is a complement of the first polynucleotide; and (c) a nucleic acid fragment of (a) or (b).
 12. A vector comprising the nucleic acid molecule of claim
 11. 13. The vector of claim 12, further comprising a promoter operably-linked to said nucleic acid molecule.
 14. A cell comprising the vector of claim
 12. 15. An antibody that binds immunospecifically to the polypeptide of claim
 1. 16. The antibody of claim 15, wherein said antibody is a monoclonal antibody.
 17. The antibody of claim 15, wherein the antibody is a humanized antibody.
 18. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising: (a) providing the sample; (b) contacting the sample with an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.
 19. A method for determining the presence or amount of the nucleic acid molecule of claim 5 in a sample, the method comprising: (a) providing the sample; (b) contacting the sample with a probe that binds to said nucleic acid molecule; and (c) determining the presence or amount of the probe bound to said nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in said sample.
 20. The method of claim 19 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.
 21. The method of claim 20 wherein the cell or tissue type is cancerous.
 22. A method of identifying an agent that binds to a polypeptide of claim 1, the method comprising: (a) contacting said polypeptide with said agent; and (b) determining whether said agent binds to said polypeptide.
 23. The method of claim 22 wherein the agent is a cellular receptor or a downstream effector.
 24. A method for identifying an agent that modulates the expression or activity of the polypeptide of claim 1, the method comprising: (a) providing a cell expressing said polypeptide; (b) contacting the cell with said agent, and (c) determining whether the agent modulates expression or activity of said polypeptide, whereby an alteration in expression or activity of said peptide indicates said agent modulates expression or activity of said polypeptide.
 25. A method for modulating the activity of the polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of said claim with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.
 26. A method of treating or preventing a GPCRX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the polypeptide of claim 1 in an amount sufficient to treat or prevent said GPCRX-associated disorder in said subject.
 27. The method of claim 26 wherein the disorder is selected from the group consisting of cardiomyopathy and atherosclerosis.
 28. The method of claim 26 wherein the disorder is related to cell signal processing and metabolic pathway modulation.
 29. The method of claim 26, wherein said subject is a human.
 30. A method of treating or preventing a GPCRX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the nucleic acid of claim 5 in an amount sufficient to treat or prevent said GPCRX-associated disorder in said subject.
 31. The method of claim 30 wherein the disorder is selected from the group consisting of cardiomyopathy and atherosclerosis.
 32. The method of claim 30 wherein the disorder is related to cell signal processing and metabolic pathway modulation.
 33. The method of claim 30, wherein said subject is a human.
 34. A method of treating or preventing a GPCRX-associated disorder, said method comprising administering to a subject in which such treatment or prevention is desired the antibody of claim 15 in an amount sufficient to treat or prevent said GPCRX-associated disorder in said subject.
 35. The method of claim 34 wherein the disorder is diabetes.
 36. The method of claim 34 wherein the disorder is related to cell signal processing and metabolic pathway modulation.
 37. The method of claim 34, wherein the subject is a human.
 38. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically-acceptable carrier.
 39. A pharmaceutical composition comprising the nucleic acid molecule of claim 5 and a pharmaceutically-acceptable carrier.
 40. A pharmaceutical composition comprising the antibody of claim 15 and a pharmaceutically-acceptable carrier.
 41. A kit comprising in one or more containers, the pharmaceutical composition of claim
 38. 42. A kit comprising in one or more containers, the pharmaceutical composition of claim
 39. 43. A kit comprising in one or more containers, the pharmaceutical composition of claim
 40. 44. A method for determining the presence of or predisposition to a disease associated with altered levels of the polypeptide of claim 1 in a first mammalian subject, the method comprising: (a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and (b) comparing the amount of said polypeptide in the sample of step (a) to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease; wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.
 45. The method of claim 44 wherein the predisposition is to a cancer.
 46. A method for determining the presence of or predisposition to a disease associated with altered levels of the nucleic acid molecule of claim 5 in a first mammalian subject, the method comprising: (a) measuring the amount of the nucleic acid in a sample from the first mammalian subject; and (b) comparing the amount of said nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.
 47. The method of claim 46 wherein the predisposition is to a cancer.
 48. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising an amino acid sequence of at least one of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and, or a biologically active fragment thereof.
 49. A method of treating a pathological state in a mammal, the method comprising administering to the mammal the antibody of claim 15 in an amount sufficient to alleviate the pathological state. 